Exosomes derived from embryonic stem cells inhibit doxorubicin and inflammation-induced pyroptosis in muscle cells

Dargani, Zahra Tavakoli; Singla, Reetu D.; Johnson, Taylor A.; Kukreja, Rakesh C.; Singla, Dinender K.

doi:10.1139/cjpp-2017-0340

Cited by 32 publications

(24 citation statements)

References 21 publications

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“…Dox has been found to induce both acute and late-onset dysfunction of the heart, eventually leading to heart failure and potentially death [ 3 , 4 ]. Dox-induced muscle toxicity (DIMT) can also cause dose-dependent muscle dysfunction; however, DIMT is associated with adverse changes to skeletal muscle tissue, leading to effects such as fatigue, atrophy, and eventually muscle cell death [ 5 – 8 ]. Significant loss in muscle can result in decreased response to treatment, worsening of prognosis, and a reduction in quality of life [ 5 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle

Merino

Singla

2018

Oxidative Medicine and Cellular Longevity

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Doxorubicin (Dox) is a potent chemotherapeutic drug known for its dose-dependent and serious adverse effects, such as cardiotoxicity and myotoxicity. Dox-induced cardiotoxicity (DIC) and muscle toxicity (DIMT) have been studied; however, the mechanisms of Dox-induced apoptosis in soleus muscle are not well defined. Our data shows that with Dox treatment, there is a significant increase in oxidative stress, apoptosis, proapoptotic protein BAX, pPTEN levels, and wnt3a and β-catenin activity (p < 0.05). Moreover, Dox treatment also resulted in decreased antioxidant levels, antiapoptotic BCL2, pAKT, p-mTOR, and endogenous levels of sFRP2 in the soleus muscle tissue (p < 0.05). Secreted frizzled-related protein 2 (sFRP2) treatment attenuated the adverse effects of DIMT and apoptosis in the soleus muscle, evidenced by a decrease in oxidative stress, apoptosis, BAX, pPTEN, and wnt3a and β-catenin activity, as well as an increase in antioxidants, BCL2, pAKT, p-MTOR, and sFRP2 levels (p < 0.05). This data suggests that Dox-induced oxidative stress and apoptosis is mediated through both the Akt-mTOR and wnt/β-catenin pathways. Moreover, the data also shows that sFRP2 modulates these two pathways by increasing signaling of Akt-mTOR and decreased signaling of the wnt/β-catenin pathway. Therefore, our data suggests that sFRP2 has valuable therapeutic potential in reversing Dox-induced oxidative stress and apoptosis in soleus muscle mediated through the Akt-mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle

Merino

Singla

2018

Oxidative Medicine and Cellular Longevity

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“… 26 In addition, exosomes have a role in inhibiting pyroptosis. 27 We found that miR-320b was significantly increased in MSCs-exo, and could target NLRP3 protein to inhibit pyroptosis to prevent I/R injury.…”

Section: Introductionmentioning

confidence: 81%

<p>Exosomes Derived from Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Inhibiting Pyroptosis</p>

Tang¹,

Jin²,

Yang³

et al. 2020

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Objective Mesenchymal stem cells (MSCs) show unique advantages in cardiomyocyte repairment. Exosomes derived from MSCs can enhance the viability of myocardial cells after ischemia/reperfusion (I/R) injury and regulate inflammation response. The study was designed to ascertain whether MSCs-exo protect the myocardium against I/R injury through inhibiting pyroptosis, and the underlying mechanisms. Methods and Results Experiments were carried out in H/R and I/R model. Cell viability was inhibited and NLRP3 and caspase1 protein levels were upregulated in H/R model. However, MSCs could inhibit cell apoptosis and pyroptosis in H/R model. Moreover, we used MSCs-exo to treated H/R model, and flow cytometric analysis results showed the inhibition function of MSCs-exo on cell apoptosis, and Western blot data suggested that NLRP3 and Caspase-1 expressions were downregulated in H/R model. Furthermore, exosomal miR-320b targeted NLRP3 protein, and MSCs-exo OE could inhibit NLRP3 expression and pyroptosis in H/R. In addition, the inhibition function of MSCs-exo on pyroptosis also was found in I/R model, and HE and Tunel staining also got similar results. Conclusion Exosomes derived from mesenchymal stem cells could protect the myocardium against ischemia/reperfusion injury through inhibiting pyroptosis.

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“…Doxo is an anthracycline antineoplastic chemotherapeutic agent with compromised medicinal utility (42,49). It has been estimated that roughly 10% of patients receiving Doxo or its derivatives will suffer adverse cardiac events, and the cardiotoxicity may present itself up to 10 -15 yr posttherapy cessation (51).…”

Section: Discussionmentioning

confidence: 99%

“…Doxorubicin (Doxo) is a commonly used anthracycline in a variety of cancer therapies for leukemias, lymphomas, breast cancer, and many carcinomas (49). Unfortunately, clinical applications using Doxo are limited due to severe, dosedependent cardiotoxic side effects.…”

Section: Introductionmentioning

confidence: 99%

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

Johnson

Singla

2018

American Journal of Physiology-Heart and Circulatory Physiology

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Doxorubicin (Doxo) is an effective agent commonly used in cancer therapeutics. Unfortunately, Doxo treatment can stimulate cardiomyopathy and subsequent heart failure, limiting use of this drug. The role of phosphatase and tensin homolog (PTEN) in apoptosis has been documented in Doxo induced cardiomyopathy (DIC) and heart failure models. However, whether direct inhibition of PTEN attenuates apoptosis, cardiac remodeling, and inflammatory M1 macrophages in DIC model remains elusive. Therefore, the current study is designed to understand effects of VO-OHpic (VO), a potent inhibitor of PTEN, in reducing apoptosis and cardiac remodeling. At D56, echocardiography was performed, which shows VO-OHpic treatment significantly (p<0.05) improves heart function. Immunohistochemistry, TUNEL, and histological staining were used to determine apoptosis, pro-inflammatory M1 macrophages, anti-inflammatory M2 macrophages, and cardiac remodeling. Our data shows a significant increase in apoptosis, hypertrophy, fibrosis, and pro-inflammatory M1 macrophages with Doxo treatment, whereas VO treatment significantly reduced apoptosis, adverse cardiac remodeling, and pro-inflammatory M1 macrophages significantly (p<0.05) compared to Doxo group. Western blotting confirmed the reduction of p-PTEN and increase in p-AKT protein expression in the Doxo+VO group. Moreover, VO administration increased anti-inflammatory M2 macrophages. Collectively, our data suggests that VO-OHpic treatment attenuates apoptosis and adverse cardiac remodeling, a process that is mediated through PTEN/AKT pathway, resulting in improved heart function in DIC.

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Exosomes derived from embryonic stem cells inhibit doxorubicin and inflammation-induced pyroptosis in muscle cells

Cited by 32 publications

References 21 publications

Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle

Secreted Frizzled-Related Protein-2 Inhibits Doxorubicin-Induced Apoptosis Mediated through the Akt-mTOR Pathway in Soleus Muscle

<p>Exosomes Derived from Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Inhibiting Pyroptosis</p>

PTEN inhibitor VO-OHpic attenuates inflammatory M1 macrophages and cardiac remodeling in doxorubicin-induced cardiomyopathy

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