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The Thioredoxin System is Regulated by the ASK-1/JNK/p38/Survivin Pathway During Germ Cell Apoptosis

Nora Al-Kandari1, Fatemah Fadel2, Farah Al-Saleh3

  • 1Department of Biochemistry, Faculty of Medicine, Kuwait University, Jabriyah 13110, Kuwait. norayaq@gmail.com.

Molecules (Basel, Switzerland)
|September 25, 2019
PubMed

Insights

Testicular ischemia reperfusion injury (tIRI) causes oxidative stress and germ cell apoptosis by disrupting the thioredoxin (Trx) system. NQDI-1 treatment protected against tIRI by modulating the ASK-1/Trx/TXNIP axis.

Area of Science:

  • Cell Biology
  • Physiology
  • Biochemistry

Background:

  • Testicular ischemia reperfusion injury (tIRI) is a significant cause of male infertility.
  • The precise molecular mechanisms underlying tIRI-induced testicular damage, particularly involving oxidative stress and apoptosis, require further elucidation.
  • The thioredoxin (Trx) system plays a crucial role in cellular redox homeostasis and has been implicated in various injury models.

Purpose of the Study:

  • To investigate the role of the apoptosis signal-regulating kinase-1 (ASK-1) signaling pathway and the thioredoxin (Trx) system in testicular ischemia reperfusion injury (tIRI).
  • To explore the therapeutic potential of the ASK-1 specific inhibitor, NQDI-1, in mitigating tIRI-induced testicular damage.
  • To elucidate the ASK-1/Trx/TXNIP axis in regulating redox homeostasis and germ cell apoptosis during tIRI.

Main Methods:

  • Male Sprague-Dawley rats were subjected to sham operation, tIRI, or tIRI with NQDI-1 treatment.
  • Histological analyses were performed to assess spermatogenesis and tissue damage.
  • Protein immunoexpression, biochemical assays (SOD, GSH), and real-time PCR were utilized to evaluate apoptosis pathways, redox status, and gene expression.

Main Results:

  • tIRI induced significant oxidative stress, characterized by decreased SOD and GSH levels, increased lipid and DNA damage, and impaired spermatogenesis.
  • tIRI activated the ASK-1/JNK/p38/survivin apoptosis pathway, evidenced by altered mRNA expression of pro- and anti-apoptotic genes and increased caspase 3 activity.
  • NQDI-1 treatment attenuated tIRI-induced oxidative stress and apoptosis, restoring normal Trx system function and reducing TXNIP expression.

Conclusions:

  • The thioredoxin (Trx) system, regulated by the ASK-1/Trx/TXNIP axis, is critical for maintaining cellular redox homeostasis during tIRI.
  • Dysregulation of the ASK-1/Trx/TXNIP axis contributes to germ cell apoptosis in tIRI.
  • Targeting the ASK-1 pathway with inhibitors like NQDI-1 may represent a promising therapeutic strategy for managing testicular ischemia reperfusion injury.
Keywords:
ASK-1JNKNQDI-1germ cell apoptosisoxidative DNA damagesurvivintesticular ischemia reperfusion injurythioredoxin

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