Thyroid cancer (TC) is the most common endocrine malignancy without reliable preventive agent. Resveratrol possesses in vitro anti-TC activities; while its effect(s) on thyroid tumorigenesis remains unknown. This study aims to address this issue using DEN/MNU/DHPN-induced rat carcinogenesis model. 50 male Sprague-Dawley rats were separated into four groups as Group-1 (5 rats); normally fed; Group-2 (15 rats); DEN/MNU/DHPN treatment only; Group-3 (15 rats) and -4 (15 rats); DEN/MNU/DHPN treatment; followed by resveratrol intragastric (IG) injection and intraperitoneal (IP) injection; respectively; in two-day intervals for 30 weeks. The results revealed that the average resveratrol concentration in thyroid tissues was 1.278 ± 0.419 nmol/g in IG group and 1.752 ± 0.398 nmol/g in IP group. The final body weights of Group-3 and Group-4 were lighter than that (p > 0.05) of Group-1; but heavier than Group-2 (p < 0.05). TC-related lesions (hyperplasia and adenomas) were found in 53.3% of Group-2; 33.3% Group-3 and 26.7% Group-4. Lower serum carcino-embryonic antigen (CEA) and thyroglobulin (Tg) levels; down-regulated expression of IL-6 and cyclooxygenase-2 (COX-2); reduction of NF-κB/p65 nuclear translocation; and elevated IkBα expression were found in the thyroid tissues of Group-3 and Group-4 in comparison with that of Group-2. These results demonstrate that IG and IP administered resveratrol efficiently reduces the frequency and severity of DEN/MNU/DHPN-caused TC-related lesions and would be of values in thyroid tumor prevention.

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2,5-hexanedione (2,5-HD) is the main active metabolite of n-hexane and induces apoptosis in nerve tissue, however, the mechanism of which remains unclear. In the present study, neuropathic animal models were successfully constructed in rats by injecting 100, 200 and 400 mg/kg 2,5-HD intraperitoneally for 5 weeks. Rats exposed to 2,5-HD exhibited progressive gait abnormalities and slower motor neural response in a dose-dependent manner. TUNEL analysis and immunofluorescence dual labeling revealed that the spinal cord of the 2,5-HD treated rats underwent significantly more apoptosis in the cells of spinal cord than that of the control group. The neuron apoptosis index in spinal cord was 4.1%, 6.7%, 9.8% respectively in rats exposed to 100, 200 and 400 mg/kg 2,5-HD, compared with 1.1% in the control group (p < 0.05). Biochemical analysis showed that 2,5-HD exposure downregulated NGF expression in the spinal cord of the intoxicated rats; inhibited the phosphorylation of Akt and Bad, two key players in PI3K/Akt pathway downstream of NGF; increased the dimerization of Bad with Bcl-xL in the mitochondrial fraction, followed by the release of cytochrome c and activation of caspase-3 in the spinal cord of rats. In vitro study showed that the NGF expression decreased significantly in VSC4.1 cells dosed with 5.0, 10.0 mM 2,5-HD in comparison with the control group. It was also found that NGF supplement repressed the induced apoptosis, and increased p-Akt and p-Bad level in 2,5-HD treated VSC4.1 cells, which could be antagonized by PI3K kinase (the upstream member of Akt) inhibitor LY294002. Taken together, our experimental results indicate that 2,5-HD may induce apoptosis in the spinal cord of rats via downregulating NGF expression and subsequently repressing PI3K/Akt signaling pathway.

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