β-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice

Sanajou, Davoud; Ahmad, Saeed Nazari Soltan; Hosseini, Vahid; Kalantary‐Charvadeh, Ashkan; Marandi, Yasser; Roshangar, Leila; Bahrambeigi, Saman; Abbasi, Mehran Mesgari

doi:10.1007/s00210-019-01619-0

Cited by 14 publications

(8 citation statements)

References 37 publications

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“…Similarly, Davoud Sanajou et al. revealed that administration of B‐LAP protects mice against DOX‐induced nephrotoxicity via modulation of cellular NAD + levels and AMPK activation . Once activated, AMPK signals to multiple downstream pathways such as Nrf2 and mTOR .…”

Section: Discussionmentioning

confidence: 98%

“…24 Similarly, Davoud Sanajou et al revealed that administration of B-LAP protects mice against DOX-induced nephrotoxicity via modulation of cellular NAD + levels and AMPK activation. 25 Once activated, AMPK signals to multiple downstream pathways such as Nrf2 and mTOR. 26 Activated AMPK promotes the translocation of the Nrf2 from cytosol to nucleus where it consequently stimulates the expression of cytoprotective genes HO-1 and NQO-1.…”

Section: Discussionmentioning

confidence: 99%

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β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

Ahmad

Sanajou

Kalantary‐Charvadeh

et al. 2019

Basic Clin Pharma Tox

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β‐LAPachone (B‐LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B‐LAP against doxorubicin (DOX)‐induced cardiotoxicity was examined in mice. Thirty‐five mice were divided into 5 groups: control group, B‐LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B‐LAP (2.5 mg/kg) group and DOX+B‐LAP (5 mg/kg) group. B‐LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B‐LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK‐MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD+/NADH ratio, B‐LAP up‐regulated the cardiac levels of SIRT1, beclin‐1, p‐LKB1 and p‐AMPK, and reduced the cardiac levels of p‐mTOR, interleukin (IL)‐1β, TNF (tumour necrosis factor)‐α and caspase‐3. B‐LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up‐regulated the protein levels of haem oxygenase (HO‐1) and glutathione S‐transferase (GST) in the hearts of DOX mice. While B‐LAP reduced malondialdehyde concentrations in heart of DOX‐treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B‐LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B‐LAP against DOX‐induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

Ahmad

Sanajou

Kalantary‐Charvadeh

et al. 2019

Basic Clin Pharma Tox

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“…We also previously showed the efficacy of β-LAP in attenuating DOX-induced cardiotoxicity and nephrotoxicity through inhibition of the inflammatory pathway and the induction of antioxidant response. [19,28] In the β-LAP induces NQO-1, in which increases the NAD + /NADH ratio. NAD + performs critical functions in energy metabolism and regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

Kalantary‐Charvadeh,

Nazari Soltan Ahmad,

Aslani

et al. 2023

J Biochem & Molecular Tox

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Doxorubicin (DOX) is a widely used antineoplastic drug, but its clinical use is limited by significant toxicities, such as hepatotoxicity. In this study, we evaluated the effects of β‐lapachone (β‐LAP), a natural quinone‐containing compound, in a mouse model of DOX‐induced hepatotoxicity. β‐LAP was orally administered at 1.25, 2.5, and 5 mg/kg for 4 days, and a single dose of DOX (20 mg/kg) was injected intraperitoneally on the second day. Histopathological changes, liver function markers, antioxidant and inflammatory markers were assessed. β‐LAP ameliorated liver injury and liver function markers evoked by DOX. β‐LAP also downregulated the mRNA expression of nuclear factor‐kB‐corresponding genes including interleukin‐6, interleukin‐1β, and tumor necrosis factor‐α. Moreover, β‐LAP increased the nuclear factor erythroid 2‐related factor 2 target genes heme oxygenase‐1 and NAD(P)H: quinone oxidoreductase 1, along with antioxidant enzymes including reduced glutathione, catalase, and superoxide dismutase with simultaneous reduction in the lipid peroxidation product malondialdehyde. Meanwhile, it recovered NAD+/NADH ratios and subsequently elevated the protein levels of sirtuin‐1 (SIRT‐1), farnesoid X receptor (FXR), and phosphorylated AMP‐activated protein kinase (p‐AMPK). Collectively, these findings suggest a protective role of β‐LAP against DOX‐induced hepatotoxicity by partly regulating the NAD+/SIRT‐1/FXR/p‐AMPK axis.

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“…DOX-chemotherapy-associated testicular damage involves an oxidative injury that is mediated by the formation of oxyradical complexes containing hydroxyl and superoxide radicals and traces of iron [ 8 ]. DOX is a well-known cytotoxic agent functioning through topoisomerase II inhibition and intercalation of DNA in rapidly developing malignant cancer cells [ 9 ]. Even though the exact underlying mechanism of DOX-induced testicular toxicity is still not fully understood, published evidence revealed that DOX-induced testicular toxicity primarily involves the combination of various pathophysiological events including oxidative stress, lipid peroxidation, inflammation, and cellular apoptosis [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats

et al. 2022

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The present study investigated the effects of α-bisabolol on DOX-induced testicular damage in rats. Testicular damage was induced in rats by injecting DOX (12.5 mg/kg, i.p., single dose) into rats. α-Bisabolol (25 mg/kg, i.p.) was administered to the rats along with DOX pre- and co-treatment daily for a period of 5 days. DOX-injected rats showed a decrease in absolute testicular weight and relative testicular weight ratio along with concomitant changes in the levels/expression levels of oxidative stress markers and Nrf2 expression levels in the testis. DOX injection also triggered the activation of NF-κB/MAPK signaling and increased levels/expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammatory mediators (iNOS and COX-2) in the testis. DOX triggered apoptosis, manifested by an increment in the expression levels of pro-apoptotic markers (Bax, Bcl2, cleaved caspase-3 and -9, and cytochrome-C) and a decline in the expression levels of anti-apoptotic markers (Bcl-xL and Bcl2) in the testis. Additionally, light microscopy revealed the changes in testicular architecture. α-Bisabolol rescued alterations in the testicular weight; restored all biochemical markers; modulated the expression levels of Nrf2-mediated antioxidant responses, NF-κB/MAPK signaling, endoplasmic reticulum (ER) stress, and apoptosis markers in DOX-injected testicular toxicity in rats. Based on our findings, it can be concluded that α-bisabolol has the potential to attenuate DOX-induced testicular injury by modifying NF-κB/MAPK signaling and the ER-stress-mediated mitochondrial pathway of apoptosis by invoking Nrf2-dependent antioxidant defense systems in rats. Based on the findings of the present study, α-bisabolol could be suggested for use as an agent or adjuvant with chemotherapeutic drugs to attenuate their deleterious effects of DOX on many organs including the testis. However, further regulatory toxicology and preclinical studies are necessary before making recommendations in clinical tests.

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β-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice

Cited by 14 publications

References 37 publications

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats

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β-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice

Cited by 14 publications

References 37 publications

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD+/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats

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β‐lapachone protects against doxorubicin‐induced hepatotoxicity through modulation of NAD⁺/SIRT‐1/FXR/p‐AMPK/NF‐kB and Nrf2 signaling axis