Alaa S. Elawady

Polystyrene nanoplastic (PSNP) contaminants are widespread in the environment with potential adverse effects on male reproductive health. This study investigated the molecular mechanisms underlying PSNP-induced testicular dysfunction in rats and evaluated the protective effects of pirfenidone (PF) and tirzepatide (TZP). Twenty-four adult albino rats were included in the study. Eighteen rats received PSNP (1.5 mg/kg/day, orally) for 8 weeks, while six age-matched rats receiving deionized water by oral gavage served as negative controls. Beginning in week 5, PSNP-exposed rats were assigned to three groups (n = 6/group): vehicle-treated PSNP, PSNP+PF (100 mg/kg/day, orally), and PSNP+TZP (0.5 mg/kg/week, subcutaneously), with treatments continued for 4 weeks. PSNP exposure impaired testicular architecture, disrupted the blood–testis barrier, compromised steroidogenesis, and promoted testicular fibrosis. It also induced oxidative stress through dysregulation of the TXNIP/TRX system and enhanced pyroptosis, potentially through activation of the HMGB1/TLR4/NF-κB/NLRP3 signaling pathway. Treatment with either PF or TZP markedly attenuated PSNP-induced alterations, preserved blood–testis barrier integrity, improved steroidogenic function, and reduced fibrosis, oxidative stress, and pyroptosis. These protective effects were associated with modulation of the TXNIP/TRX system and suppression of HMGB1/TLR4/NF-κB/NLRP3-mediated pyroptotic signaling. Collectively, these findings identify PF and TZP as promising preclinical candidates for mitigating PSNP-induced testicular toxicity. Further mechanistic and translational studies are warranted to validate their potential role in protecting male reproductive health.

The present study aimed to illustrate the hypolipemic effect of 10-Dehydrogengardione (10-DHG) or caffeic acid (CA) with reference to the role of microRNA-122 (miR-122) and ATP citrate lyase (ACLY) activity. Diabetic hyperlipidemia was induced in rats, and then randomly classified into three groups. The first one received only a CCT-diet for 6 weeks and was referred to as the positive control. The other two groups received 10-DHG (10 mg/kg/day) or CA (50 mg/kg/day), orally for 6 weeks along with a CCT-diet. Another group of normal rats was included, received a normal diet, and was referred to as the negative control. Either 10-DHG or CA significantly decreased MiR-122 expression and appeared more remarkable in the CA group by 15.5%. The 10-DHG greatly enhanced phosphorylated form of AMP activated protein kinase (p-AMPK) activity, more than CA by 1.18-fold, while the latter exerted more inhibitory effect on ACLY, and fatty acid synthase (FAS) activities compared with 10-DHG (p < 0.05). Both drugs significantly decreased hydroxy methyl glutaryl coenzyme A (HMG-COA) reductase activity, which appeared more remarkable in 10-DHG, and significantly decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) along with a high density lipoprotein cholesterol (HDL-C) increase. The 10-DHG ameliorated the hepatic tissue lesions greatly, more than CA. The 10-DHG or CA significantly inhibited MiR-122, hepatic FAS, and ACLY levels along with p-AMPK activation. This subsequently led to reduced plasma TG, cholesterol levels, and blood glucose improvement and, indeed, may explain their mechanisms as hypolipemic agents.