Tranilast abrogates cisplatin‐induced testicular and epididymal injuries: An insight into its modulatory impact on apoptosis/proliferation

Abstract

Cisplatin is a chemotherapeutic agent whose therapeutic use is greatly limited by the associated organs' toxicity and particularly, testicular toxicity. Cisplatin‐induced testicular damage reported being mediated through mitochondria‐mediated apoptosis, inflammation, and oxidative stress. Evidence showed that tranilast (TRN) has the ability to restore the oxidative status and modulate TRAIL/caspase‐8 signaling. This led us to hypothesize that TRN could abrogate cisplatin‐induced testicular and epididymal injuries via inhibiting oxidative stress and modulating proliferation and TRAIL/caspase‐8/cJNK signaling. Cisplatin injection induced oligospermia and abnormalities in testicular and epididymal structure along with impaired oxidative status. TRN administration (100 or 300 mg/kg) for 7 days post‐cisplatin injection preserved spermatogenesis and restored testicular and epididymal architecture, but restoration was more so in TRN300 than TRN100. This was in line with the restoration of balanced oxidative status as indicated by the increased total antioxidant capacity, glutathione and superoxide dismutase activity, and the decreased malondialdehyde content in testes (p < 0.05 vs. cisplatin). TRN increased the cell proliferation revealed by the increased expression of proliferating cell nuclear antigen in a dose‐dependent manner (p < 0.05 vs. cisplatin) whereas only TRN300 decreased testicular cJNK, TRAIL, and caspase‐8 expression (p < 0.05 vs. cisplatin). Moreover, TRN dose‐dependently inhibited the pro‐inflammatory transcription factor NF‐kB and the cytokine TNF‐α expressions in testes. In conclusion, TRN300 was more effective than TRN100 in alleviating cisplatin‐induced testicular and epididymal injuries and in enhancing spermatogenesis. This curative effect of TRN might be mediated through its antioxidant and anti‐inflammatory impacts along with its modulatory impact on cJNK/TRAIL/caspase‐8 signaling favoring proliferation rather than apoptosis.

Roles of adipose-derived stem cells and derived exosomes in therapeutic applications to testicular injury caused by cisplatin

“…In addition, cisplatin can activate the Nuclear factor kappa-B (NF-κB) signaling pathway and increase the expression of pro-inflammatory cytokines, leading to inflammation and tissue damage [ 19 ]. Furthermore, cisplatin can directly damage DNA and induce apoptosis in testicular cells [ 15 ].…”

“…The animal model of testicular cell damage was established by intraperitoneal injection of a 10mg/kg cisplatin solution. Three days after modeling, the testicular cell damage model + cell therapy group received a tail vein injection of 3*10^6 CM-DiI-labeled ADSCs cells, while the testicular cell damage model + Ex group received a tail vein injection of 100μg of ADSC-Ex The normal control group and the testicular cell damage model group received an equal volume of saline via tail vein injection [13][14][15]. The procedures of Dil labeling were as follow: remove the supernatant from the culture dish and replace it with serumfree basal medium dulbecco's modified eagle medium/nutrient mixture F-12 (DMEM/F12) for cell cultivation.…”

The Effects of White Tea (Camellia Sinensis) and Infliximab Against Cisplatin- Induced Testicular Damage via Oxidative Stress and Apoptosis

“…The resulting ROS cause an increase in the production of proinflammatory cytokines (Tian et al, 2018). Elevated levels of proinflammatory cytokines, particularly of TNFα, result in the activation of the nuclear factor-κB (NF-κB) signaling pathway, which leads to inflammation and apoptosis (Makled & Said, 2021). High levels of TNF-α also accelerate inflammation by increasing the production…”

“…Cisplatin-induced oxidative stress causes an increase in the levels of proinflammatory cytokines that lead to the activation of the nuclear factor-κB (NF-κB) signaling pathway, which is the primary mediator of the inflammatory response (Habib et al, 2019;Makled & Said, 2021). Tumor necrosis factor-α (TNF-α) is one of the most important proinflammatory cytokines that induce apoptosis by triggering cell damage (Li et al, 2006;Moradi et al, 2021).…”