The aim of the study was to investigate the protective effect of pyrrolidine dithiocarbamate (PDTC) against methotrexate (MTX)-induced testicular damage in rats. Forty Wistar albino male rats were divided into equally four groups: Control group (saline solution, IP), PDTC group (100 mg/kg PDTC,IP, 10 days), MTX group (20 mg/kg MTX, IP, single dose, on the 6th day) and MTX + PDTC group (100 mg/kg PDTC, IP, 10 days and 20 mg/kg MTX, IP, single dose, on the 6th day). After 10 days, testicular tissues were excised for morphometric, histological and immunohistochemical evaluations. Serum testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH) and prokineticin 2 (PK2) levels were determined. Body and testicular weights were measured. Testicular damage was assessed by histological evaluation. Nuclear factor kappa B (NFkB), nuclear factor erythroid 2 related factor 2 (Nrf2) and PK2 immunoreactivities were evaluated by HSCORE. Body and testicular weights, serum FSH, LH, testosterone levels, seminiferous tubule diameter and germinal epithelial thickness were significantly decreased in the MTX group. However, serum PK2 level, histologically damaged seminiferous tubules and interstitial field width were significantly increased. Additionally, there was an increase in NFkB and PK2 immunoreactivity, whereas there was a significant decrease in Nrf2 immunoreactivity. PDTC significantly improved hormonal, morphometric, histological and immunohistochemical findings. Taken together, we conclude that PDTC may reduce MTX-induced testicular damage via NFkB, Nrf2 and PK2 signaling pathways.

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This study aimed to clarify the role of crosstalk between discoidin domain receptors (DDRs) and matrix metalloproteinases (MMPs) in the ligamentum flavum (LF) fibrosis obtained from patients with degenerative lumbar canal stenosis (DLCS). Overview of Literature: The DDRs, DDR1 and DDR2, are cell surface receptors and have an essential role in collagen fiber accumulation in several fibrotic diseases. MMPs are one of the critical factors in extracellular matrix remodeling and elastic fiber degradation in LF tissues. However, the crosstalk between DDRs and MMPs and the role of this molecular signal in LF fibrosis remain unclear. Methods: A total of 35 patients were divided into two groups in this study. Spinal surgery was performed in 23 of these patients with the diagnosis of DLCS. Twelve patients with lumbar disk herniation (LDH) were included in the control group. On axial T2-weighted magnetic resonance imaging, LF thickness was measured bilaterally at the level of the facet joint. Histology, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analyses were performed on LF tissue samples. LF tissues were stained with hematoxylin and eosin. In addition, the grade of fibrosis was histologically assessed using Masson trichrome triple staining. DDR1 and DDR2 Western blot analyses were performed. DDR1, DDR2, MMP2, MMP3, MMP9, and MMP13 expression levels were measured using qRT-PCR analysis. Results: The grade of fibrosis and LF thickness were significantly higher in the DLCS patients than in the LDH patients. DDR1 and DDR2 gene expression and protein levels in LF tissues are significantly greater in DLCS samples than in control samples, according to both qRT-PCR and Western blot analyses. In addition, we detected a significant expression of the MMP3, MMP9, and MMP13, which are known to have important roles in extracellular matrix remodeling in DLCS. Furthermore, we discovered a link between DDR protein levels and LF thickness, fibrosis, and MMP3/MMP9. Conclusions: Our results indicate that DDR1, DDR2, and MMP3 and MMP9 signals can be correlated with each other in LF tissues and be promoted LF fibrosis leading to spinal canal narrowing in patients with DLCS.

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