CBLB502, a Toll-like receptor 5 agonist, offers protection against radiation-induced male reproductive system damage in mice†

Abstract

CBLB502, a Toll-like receptor (TLR)5 agonist derived from Salmonella flagellin, was shown to protect mammalian hematopoietic and gastrointestinal systems from acute irradiation syndrome and to stimulate regeneration. To explore whether CBLB502 can improve testicular injuries caused by irradiation, mice were intraperitoneally injected with 0.2 mg/kg CBLB502 or vehicle control 30 min prior to applying 5.0 Gy ionizing radiation (IR). We observed these mice for the following 120 days and determined that CBLB502 pretreatment alleviated IR-induced oxidative stress, alleviated the distorted architecture of seminiferous tubules, reversed the decline of sperm quantity and quality, and helped recover male mouse fertility. Additionally, CBLB502 efficiently reduced DNA damage and chromosomal aberrations in IR-treated mice and their offspring. Due to the suppression of p53-dependent apoptosis, in IR-treated mice, CBLB502 was shown to significantly activate the nuclear factor kappa B (NFκB) pathway and reduce the apoptotic rate in association with an increase in anti-apoptotic B-cell lymphoma (BCL)2 levels and a decrease in the levels of DNA repair protein and proliferating cell nuclear antigen (PCNA). Moreover, an IR-induced reduction in serum testosterone and superoxide dismutase (SOD) levels and an increase in malondialdehyde (MDA) levels were considerably reversed in CBLB502-pretreated mice. No significant reverse effects were found in Tlr5 knockout mice, suggesting that protection of the testis against IR by CBLB502 is primarily dependent on the TLR5 signaling pathway. Our results may help further investigations into potential CBLB502 applications for the protection of the male reproductive system during radiotherapy.

Heat‐killed Salmonella typhimurium mitigated radiation‐induced lung injury

“…In recent years, the protective roles of Toll‐like receptors (TLRs) have drawn more and more attention. The latest research showed that CBLB502, a TLR5 agonist derived from Salmonella flagellin , effectively protected mammalian haematopoietic and gastrointestinal systems from acute irradiation syndrome . Our previous studies have also proved that activation of TLR2 and TLR4 significantly protected mice and cultured cells against ionizing radiation.…”

RNA Profiling Reveals a Common Mechanism of Histone Gene Downregulation and Complementary Effects for Radioprotectants in Response to Ionizing Radiation

“…Specifically, most altered miRNAs, lncRNAs, and mRNAs were either co-upregulated or co-downregulated (71, 3606, and 1051, respectively) between the CBLB502 and amifostine groups, with only a few showing opposite trends of change (1.39%, 0.36%, and 0.76%, respectively) ( Table 2). In contrast, although there were several co-regulated miRNAs, lncRNAs, and mRNAs between the amifostine and nilestriol groups (46,1107, and 591, respectively), higher percentages of altered RNAs were found in the opposite regulatory direction (9.80%, 16.45%, and 4.68%, respectively), indicating the different regulatory patterns between these 2 radioprotectants. Similarly, 14.89%, 17.44%, and 5.42% of the respective RNAs in the opposite regulatory direction showed different patterns between the CBLB502 and nilestriol groups (Table 2).…”

“…Although the mechanisms of amifostine and CBLB502mediated radioprotection are poorly understood, 39 they are both likely to have a cytoprotective effect and rapid response against IR-induced stress within several hours, 5,40 with achieving complex radiation-cytoprotective effects by interfering with genes involved in scavenging free radicals, cell cycle regulation, apoptosis, and inflammation. 6,7,[41][42][43][44][45][46] However, nilestriol requires a longer time, usually hours or days, to exert its protective effects, and its post-irradiation mechanism does not involve primary radiation-induced cellular processes. 3,9 These differences in reaction time and mechanism may explain the similarities between amifostine and CBLB502 in terms of the influence on IR-induced RNAs, which was distinct from that of nilestriol.…”

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies

“…CBLB502 was also stated to reestablish testicular antioxidant condition and decrease testicular oxidative injury caused by IR [ 66 ]. To evaluate if CBLB502 can reduce testicular damage, animals were intraperitoneally injected with CBLB502 prior to applying IR [ 67 ]. It was reported that CBLB502 administration reduced IR-provoked oxidative stress, decreased the alterations of architecture of seminiferous tubules, increased the sperm quality and quantity, and ameliorated male mouse fertility.…”

“…Furthermore, an IR-caused decrease in serum testosterone and superoxide dismutase (SOD) concentrations and an augmentation in malondialdehyde (MDA) concentrations were significantly inverted in CBLB502-pretreated animals. No relevant actions were reported in TLR5 knockout mice, proposing that defense of the testis against IR by CBLB502 is essentially due to the TLR5 signaling pathway [ 67 ].…”