Role of Na+-K+-Cl− cotransport and Na+/Ca2+ exchange in mitochondrial dysfunction in astrocytes following in vitro ischemia

Na+-K+-Cl− cotransporter isoform 1 (NKCC1) and reverse mode operation of the Na+/Ca2+ exchanger (NCX) contribute to intracellular Na+ and Ca2+ overload in astrocytes following oxygen-glucose deprivation (OGD) and reoxygenation (REOX). Here, we further investigated whether NKCC1 and NCX play a role in mitochondrial Ca2+ (Cam2+) overload and dysfunction. OGD/REOX caused a doubling of mitochondrial-releasable Ca2+ ( P < 0.05). When NKCC1 was inhibited with bumetanide, the mitochondrial-releasable Ca2+ was reduced by ∼42% ( P < 0.05). Genetic ablation of NKCC1 also reduced Cam2+ accumulation. Moreover, OGD/REOX in NKCC1+/+ astrocytes caused dissipation of the mitochondrial membrane potential (Ψm) to 42 ± 3% of controls. In contrast, when NKCC1 was inhibited with bumetanide, depolarization of Ψm was attenuated significantly (66 ± 10% of controls, P < 0.05). Cells were also subjected to severe in vitro hypoxia by superfusion with a hypoxic, acidic, ion-shifted Ringer buffer (HAIR). HAIR/REOX triggered a secondary, sustained rise in intracellular Ca2+ that was attenuated by reversal NCX inhibitor KB-R7943. The hypoxia-mediated increase in Cam2+ was accompanied by loss of Ψm and cytochrome c release in NKCC1+/+ astrocytes. Bumetanide or genetic ablation of NKCC1 attenuated mitochondrial dysfunction and astrocyte death following ischemia. Our study suggests that NKCC1 acting in concert with NCX causes a perturbation of Cam2+ homeostasis and mitochondrial dysfunction and cell death following in vitro ischemia.

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Stimulation of astrocyte Na+/H+ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2

AJP Cell Physiology ◽

10.1152/ajpcell.00092.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. C934-C945 ◽

Cited By ~ 33

Author(s):

Douglas B. Kintner ◽

Andy Look ◽

Gary E. Shull ◽

Dandan Sun

Keyword(s):

Glucose Deprivation ◽

Oxygen And Glucose Deprivation ◽

In Vitro Ischemia ◽

Reverse Mode ◽

Intracellular Ca ◽

Nhe1 Activity ◽

Underlying Mechanisms ◽

Stimulation Of

We recently reported that Na+/H+ exchanger isoform 1 (NHE1) activity in astrocytes is stimulated and leads to intracellular Na+ loading after oxygen and glucose deprivation (OGD). However, the underlying mechanisms for this stimulation of NHE1 activity and its impact on astrocyte function are unknown. In the present study, we investigated the role of the ERK1/2 pathway in NHE1 activation. NHE1 activity was elevated by ∼75% in NHE1+/+ astrocytes after 2-h OGD and 1-h reoxygenation (REOX). The OGD/REOX-mediated stimulation of NHE1 was partially blocked by 30 μM PD-98059. Increased expression of phosphorylated ERK1/2 was detected in NHE1+/+ astrocytes after OGD/REOX. Moreover, stimulation of NHE1 activity disrupted not only Na+ but also Ca2+ homeostasis via reverse-mode operation of Na+/Ca2+ exchange. OGD/REOX led to a 103% increase in intracellular Ca2+ concentration ([Ca2+]i) in NHE1+/+ astrocytes in the presence of thapsigargin. Inhibition of NHE1 activity with the NHE1 inhibitor HOE-642 decreased OGD/REOX-induced elevation of [Ca2+]i by 73%. To further investigate changes of Ca2+ signaling, bradykinin-mediated Ca2+ release was evaluated. Bradykinin-mediated intracellular Ca2+ transient in NHE1+/+ astrocytes was increased by ∼84% after OGD/REOX. However, in NHE1−/− astrocytes or NHE1+/+ astrocytes treated with HOE-642, the bradykinin-induced Ca2+ release was increased by only ∼34%. Inhibition of the reverse mode of Na+/Ca2+ exchange abolished OGD/REOX-mediated Ca2+ rise. Together, our data suggest that ERK1/2 is involved in activation of NHE1 in astrocytes after in vitro ischemia. NHE1-mediated Na+ accumulation subsequently alters Ca2+ homeostasis via Na+/Ca2+ exchange.

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Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

Scientific Reports ◽

10.1038/s41598-021-89978-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Donita L. Garland ◽

Eric A. Pierce ◽

Rosario Fernandez-Godino

Keyword(s):

Macular Degeneration ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Deposit Formation ◽

Genetic Ablation ◽

Age Related ◽

Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

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Regulation of intracellular calcium in N1E-115 neuroblastoma cells: the role of Na+/Ca2+exchange

AJP Cell Physiology ◽

10.1152/ajpcell.00182.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. C1000-C1008 ◽

Cited By ~ 3

Author(s):

Kara L. Kopper ◽

Joseph S. Adorante

Keyword(s):

Membrane Potential ◽

Intracellular Calcium ◽

Normal Cell ◽

Buffer Capacity ◽

Neuroblastoma Cells ◽

Fold Increase ◽

Scorpion Venom ◽

Reverse Mode ◽

Intracellular Ca

In fura 2-loaded N1E-115 cells, regulation of intracellular Ca2+ concentration ([Ca2+]i) following a Ca2+ load induced by 1 μM thapsigargin and 10 μM carbonylcyanide p-trifluoromethyoxyphenylhydrazone (FCCP) was Na+ dependent and inhibited by 5 mM Ni2+. In cells with normal intracellular Na+ concentration ([Na+]i), removal of bath Na+, which should result in reversal of Na+/Ca2+exchange, did not increase [Ca2+]i unless cell Ca2+ buffer capacity was reduced. When N1E-115 cells were Na+ loaded using 100 μM veratridine and 4 μg/ml scorpion venom, the rate of the reverse mode of the Na+/Ca2+ exchanger was apparently enhanced, since an ∼4- to 6-fold increase in [Ca2+]ioccurred despite normal cell Ca2+ buffering. In SBFI-loaded cells, we were able to demonstrate forward operation of the Na+/Ca2+ exchanger (net efflux of Ca2+) by observing increases (∼ 6 mM) in [Na+]i. These Ni2+ (5 mM)-inhibited increases in [Na+]i could only be observed when a continuous ionomycin-induced influx of Ca2+ occurred. The voltage-sensitive dye bis-(1,3-diethylthiobarbituric acid) trimethine oxonol was used to measure changes in membrane potential. Ionomycin (1 μM) depolarized N1E-115 cells (∼25 mV). This depolarization was Na+dependent and blocked by 5 mM Ni2+ and 250–500 μM benzamil. These data provide evidence for the presence of an electrogenic Na+/Ca2+ exchanger that is capable of regulating [Ca2+]i after release of Ca2+ from cell stores.

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Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01148.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. H1183-H1187 ◽

Cited By ~ 39

Author(s):

Kristen M. Park ◽

Mario Trucillo ◽

Nicolas Serban ◽

Richard A. Cohen ◽

Victoria M. Bolotina

Keyword(s):

Carotid Arteries ◽

Cerebral Arteries ◽

Present Evidence ◽

Voltage Gated ◽

Functional Inhibition ◽

Intracellular Ca ◽

Dependent Pathway ◽

Secondary Activation

Store-operated channels (SOC) and store-operated Ca2+ entry are known to play a major role in agonist-induced constriction of smooth muscle cells (SMC) in conduit vessels. In microvessels the role of SOC remains uncertain, in as much as voltage-gated L-type Ca2+ (CaL2+) channels are thought to be fully responsible for agonist-induced Ca2+ influx and vasoconstriction. We present evidence that SOC and their activation via a Ca2+-independent phospholipase A2 (iPLA2)-mediated pathway play a crucial role in agonist-induced constriction of cerebral, mesenteric, and carotid arteries. Intracellular Ca2+ in SMC and intraluminal diameter were measured simultaneously in intact pressurized vessels in vitro. We demonstrated that 1) Ca2+ and contractile responses to phenylephrine (PE) in cerebral and carotid arteries were equally abolished by nimodipine (a CaL2+ inhibitor) and 2-aminoethyl diphenylborinate (an inhibitor of SOC), suggesting that SOC and CaL2+ channels may be involved in agonist-induced constriction of cerebral arteries, and 2) functional inhibition of iPLA2β totally inhibited PE-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries, whereas K+-induced Ca2+ influx and vasoconstriction mediated by CaL2+ channels were not affected. Thus iPLA2-dependent activation of SOC is crucial for agonist-induced Ca2+ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries. We propose that, on PE-induced depletion of Ca2+ stores, nonselective SOC are activated via an iPLA2-dependent pathway and may produce a depolarization of SMC, which could trigger a secondary activation of CaL2+ channels and lead to Ca2+ entry and vasoconstriction.

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Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2005 ◽

2007 ◽

Vol 292 (4) ◽

pp. L915-L923 ◽

Cited By ~ 10

Author(s):

Jaime Chávez ◽

Patricia Segura ◽

Mario H. Vargas ◽

José Luis Arreola ◽

Edgar Flores-Soto ◽

...

Keyword(s):

Substance P ◽

Guinea Pigs ◽

Smooth Muscle Contraction ◽

In Vivo Experiments ◽

Intracellular Ca ◽

Neurokinin 1 ◽

Substance P Release

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+ measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, ω-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of ∼50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P.

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Synthesis, Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models

Molecules ◽

10.3390/molecules26041127 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1127 ◽

Cited By ~ 1

Author(s):

Beatriz Chamorro ◽

David García-Vieira ◽

Daniel Diez-Iriepa ◽

Estíbaliz Garagarza ◽

Mourad Chioua ◽

...

Keyword(s):

Antioxidant Activity ◽

Antioxidant Activities ◽

Antioxidant Properties ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Human Neuroblastoma ◽

In Vitro Ischemia ◽

Lipoxygenase Inhibition ◽

Antioxidant Agent

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC50 = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC50 = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.

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Intracellular calcium levels in the Plasmodium berghei ookinete

Parasitology ◽

10.1017/s0031182008004939 ◽

2008 ◽

Vol 135 (12) ◽

pp. 1355-1362 ◽

Cited By ~ 6

Author(s):

I. SIDÉN-KIAMOS ◽

C. LOUIS

Keyword(s):

Intracellular Calcium ◽

Plasmodium Berghei ◽

Calcium Concentration ◽

Insect Cells ◽

Ionophore A23187 ◽

Rodent Malaria Parasite ◽

Calcium Indicators ◽

Intracellular Ca

SUMMARYOokinetes are the motile and invasive stages of Plasmodium parasites in the mosquito host. Here we explore the role of intracellular Ca2+ in ookinete survival and motility as well as in the formation of oocysts in vitro in the rodent malaria parasite Plasmodium berghei. Treatment with the Ca2+ ionophore A23187 induced death of the parasite, an effect that could be prevented if the ookinetes were co-incubated with insect cells before incubation with the ionophore. Treatment with the intracellular calcium chelator BAPTA/AM resulted in increased formation of oocysts in vitro. Calcium imaging in the ookinete using fluorescent calcium indicators revealed that the purified ookinetes have an intracellular calcium concentration in the range of 100 nm. Intracellular calcium levels decreased substantially when the ookinetes were incubated with insect cells and their motility was concomitantly increased. Our results suggest a pleiotropic role for intracellular calcium in the ookinete.

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Knockdown of PGM1 Synergistically Enhances Anticancer Effects of Orlistat in Gastric Cancer Under Glucose Deprivation

10.21203/rs.3.rs-650761/v1 ◽

2021 ◽

Author(s):

Bo Cao ◽

Huan Deng ◽

Hao Cui ◽

Ruiyang Zhao ◽

Hanghang Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Enrichment Analysis ◽

Glucose Deprivation ◽

Metabolic Reprogramming ◽

The Cancer Genome Atlas

Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. MethodsCorrelation and enrichment analysis of PGM1 was conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed for correlations between PGM1 expression and survival time of GC patients. CCK-8, EdU, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and detection of lipid regulators levels by western blot were used to reflect on the cell lipid metabolism. ResultsCorrelation and enrichment analysis suggested that PGM1 was closely associated with cell proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients, which was also correlated with some clinicopathological features, including T stage and TNM stage. Under low glucose conditions, knockdown of PGM1 significantly suppressed cell proliferation and glycolysis levels, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity for obesity treatment, effectively induced apoptosis, suppressed FASN activity. However, orlistat conversely increased glycolytic levels in GC cells. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism. ConclusionsDownregulation of PGM1 expression under glucose deprivation synergistically enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

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Abstract 269: Cardiac Specific Disruption of Drp-1 Causes the Development of Cardiac Dysfunction via Inhibition of Autophagy and Induction of Apoptosis

Circulation Research ◽

10.1161/res.113.suppl_1.a269 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Yoshiyuki Ikeda ◽

Junichi Sadoshima

Keyword(s):

Mitochondrial Dysfunction ◽

Systolic Function ◽

Mitochondrial Fission ◽

Mitochondrial Mass ◽

Reduced Ejection Fraction ◽

Tibia Length ◽

Cardiac Systolic Function

Fission and fusion affect mitochondrial turnover in part by modulating mitophagy. This study aimed to clarify the role of mitochondrial fission in regulating cardiac function and autophagy in the heart. Dynamin-related protein 1 (Drp-1) plays an essential role in mediating mitochondrial fission. Therefore, we generated cardiac specific Drp-1 KO mice and utilized cultured cardiomyocytes transduced with adenovirus harboring short hairpin Drp-1 (Ad-shDrp-1) to test the effect of Drp-1 disruption both in vivo and in vitro. In Drp-1 KO hearts we observed a significantly greater mitochondrial mass ratio compared to control, as assessed by electron microscopy (Drp-1 KO: 3.57 ± 1.38, control: 1.18 ± 0.31, P<0.05). Mitochondrial ATP content was significantly lower (0.70 ± 0.07 vs 1.03 ± 0.10, P<0.05), while mitochondrial swelling was significantly greater (% decrease in absorbance; 8.01 ± 1.99 vs 2.01 ± 0.58, P<0.05) in Drp-1 KO hearts versus control. Mitochondrial membrane potential, assessed by JC-1 staining, was significantly reduced in myocytes with knockdown of Drp-1. Taken together, these results suggest that inhibition of fission causes mitochondrial dysfunction. We also examined the effect of Drp-1 depletion on autophagy. We found that the amount of LC-3 II was significantly less (0.47 ± 0.16 vs 1.32 ±0.34, P<0.05), whereas p62 expression was significantly greater (1.14 ± 0.16 vs 0.16 ± 0.06, P<0.01) in Drp-1 KO hearts compared to control. The number of LC3 dots in Ad-shDrp-1 transduced myocytes was lower than that of sh-scramble treatment. We investigated apoptosis and found that the amount of cleaved caspase-3 (0.62 ± 0.24 vs 0.18 ± 0.04, P<0.05) and the number of TUNEL positive cells (0.22 ± 0.12 vs 0.03 ± 0.06%, P<0.01) were higher in Drp-1 KO versus control hearts. Cardiac systolic function was reduced (ejection fraction; 44.5 ± 6.3 vs 85.4 ± 5.7%, P<0.01) and LVW/tibia length was greater (4.48 ± 0.38 vs 3.84 ± 0.58, P<0.05) in Drp-1 KO mice compared to control. Finally, we observed that the survival rate of Drp-1 KO mice was significantly reduced compared to control mice. Our results demonstrate that inhibition of mitochondrial fission via disruption of Drp-1 inhibits autophagy and causes mitochondrial dysfunction, thereby promoting cardiomyopathy.

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Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling

Bioscience Reports ◽

10.1042/bsr20190229 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 2

Author(s):

Mingfang Ye ◽

Linlin Zhang ◽

Yuanming Yan ◽

Huizhong Lin

Keyword(s):

Wide Spectrum ◽

Critical Role ◽

Antitumor Agent ◽

Cytochrome C Release ◽

Beneficial Effects ◽

H9c2 Cardiomyocytes ◽

Underlying Mechanisms ◽

Interfering Rna

Abstract Doxorubicin (DOX) is a wide-spectrum antitumor agent, but its clinical application is largely limited by its cardiotoxicity. Therefore, identification of effective agents against DOX-induced cardiotoxicity is of critical importance. The present study aimed to determine the beneficial role of punicalagin (PUN), a polyphenol isolated from pomegranate, in DOX-induced cardiotoxicity in vitro and explored the underlying mechanisms. H9c2 cardiomyocytes were pretreated with different concentrations (50, 100 and 200 μM) of PUN prior to DOX exposure. The results showed that PUN pretreatment significantly increased cell viability, inhibited lactate dehydrogenase (LDH) release and suppressed cell apoptosis induced by DOX. Additionally, PUN pretreatment attenuated the loss of mitochondrial membrane potential and cytochrome c release. Besides, PUN further enhanced the expression of nuclear Nrf2 and HO-1 in DOX-treated H9c2 cells, and the aforementioned beneficial effects of PUN were partially abolished by small interfering RNA (siRNA)-mediated Nrf2 knockdown. Hence, our findings clearly revealed that PUN might be a promising agent for alleviating the cardiotoxicity of DOX, and Nrf2/HO-1 signaling might serve a critical role during this process.

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