Hepatic iron overload is a common complication of human chronic liver diseases, including liver cirrhosis; however, the underlying mechanisms remain unclear. In the present study, we investigated the temporal changes in iron metabolism and the expression of iron-regulatory molecules during thioacetamide-induced liver cirrhosis in rats. Histopathological and biochemical analyses revealed that iron overload develops concurrently with the suppression of hepcidin expression in advanced cirrhosis. Hepatic expression of genes involved in cellular iron intake, storage, and export increased persistently in cirrhotic livers. The IL6-STAT3 and BMP6-SMAD pathways, which are the major intracellular mechanisms that induce hepcidin transcription, were inactivated in advanced cirrhosis. Furthermore, microRNA-135b-5p (miR-135b-5p), which targets JAK2 and SMAD5, key molecules of the IL6-STAT3 and BMP6-SMAD pathways, respectively, was highly upregulated in parallel with the progression of cirrhosis. These results indicate that inactivation of multiple hepcidin pathways, possibly mediated by miR-135b-5p upregulation, is responsible for hepatic iron overload in advanced cirrhosis. Our findings provide new insights into the mechanisms underlying iron dysregulation in liver cirrhosis.

This study investigated the effects on ovarian development in adult rats irradiated with γ-rays at fetal, neonatal, weaning, and early sexual maturation. Female Fischer-344 (F344) rats mated with male rats and their F1 offspring were irradiated with a single dose of 0.5 or 2 Gy of γ-rays on gestation day 15 or 19 (GD15 or 19), or postnatal day 5, 20, or 49 (PND5, 20, or 49). F1 females were reared until 27 weeks of age and necropsied. HE-stained specimens of the reproductive organs were prepared for histological examination (n=10–22 per group). The corpus luteum and follicle numbers were also counted in all ovaries. In addition, PCNA-stained specimens were used to count the primordial follicles. At 2 Gy, corpora lutea and follicle depletion was observed in the GD15, PND5, and PND20 irradiation groups. Instead of lost follicles consisting of granulosa cells, numerous tubular structures composed of Sertoli-like cells similar to those found in the testes were noted. In the GD19 group, the ovaries showed less sensitivity to γ-rays. In the PND49 irradiation group, the number of corpora lutea was normal; however, the number of follicles, including primordial follicles, decreased. At 0.5 Gy, the ovaries appeared histologically normal in all the groups; however, the number of follicles decreased in the GD15 and PND5 irradiation groups. In conclusion, we found that the timing of γ-ray irradiation significantly affected subsequent ovarian development, and the degree of change depended on the γ-ray dose.

In March 2024, a health hazard associated with the consumption of food products containing red yeast rice (beni-koji), which could lead to renal dysfunction, was reported in Japan. Puberulic acid (PA) was identified as an unintentional contaminant in these products; however, information on PA toxicity remains limited. The toxicological profile of PA was evaluated in a 28-day subacute toxicity study in rats. Synthesized PA, was administrated by gavage to 6-week-old Crl:CD(SD) rats at 0, 1, 3, or 10 mg/kg/day (male) or 0, 0.3, 1, or 3 mg/kg/day (female) over 28 days, and satellite groups were used to evaluate the reversibility over a 14-day period. Male rats in the 10 mg/kg group exhibited increased urinary glucose and serum creatinine levels compared to controls. Histopathological examination revealed vacuolation, necrosis, and regeneration of proximal tubules in kidneys of all rats in the male 10 mg/kg and female 3 mg/kg groups. After the 14-day recovery period, focal interstitial fibrosis was observed in one male rats from the high-dose group, whereas no renal lesions were detected in the remaining rats of either sex. These results suggest that PA-induced nephrotoxicity is largely reversible under the conditions studied, although residual chronic lesions may occur in severe cases. Apoptosis/necrosis and diffuse hyperplasia of the glandular stomach mucosa were observed in male 3 and 10 mg/kg and female 3 mg/kg groups but were absent after the recovery period. These results indicate that, under the study conditions, the no-observed-adverse-effect level for PA was 1 mg/kg/day for both sexes.

Canine generalized ceroid lipofuscinosis (GCL) is a rare disease characterized by the deposition of lipofuscin in systemic organs and tissues. In this case report, we encountered a dog with GCL and performed a detailed histopathological examination. A 7-year-old male beagle was euthanized due to progressive weight loss and loose or bloody stools, without any neurological symptoms. Histopathologically, deposition of lipofuscin was observed in the parenchymal cells of systemic organs, particularly in the pancreatic acini and intestinal smooth muscle, accompanied by interstitial infiltration of macrophages. No neuronal loss was observed in the central nervous system, despite such findings and neurological symptoms being commonly associated with GCL. However, some lipofuscin deposition was evident in systemic organs, so the present case was diagnosed as GCL characterized by predominant deposition in the pancreatic acini and intestinal smooth muscle. This detailed description of the morphological features may contribute to a deeper understanding of lipofuscinosis.

Drug-induced liver injury is a major reason for the discontinuation of drug development. Autophagy is a self-digestive process in the cell and can suppress cell death by removing damaged organelle from the cell. It is known that autophagy can modify drug-induced liver injury; however, details of the effects of autophagy modulation on chemically-induced hepatotoxicity are unclear. In this study, we investigated the influence of autophagy induction by rapamycin or inhibition by chloroquine on carbon tetrachloride (CCl₄)- or allyl alcohol (AA)-induced acute liver injury. Ten- to eleven-week-old male F344 rats were administrated with CCl₄ or AA after pretreatment by rapamycin or chloroquine, and were sampled 18 hours after the hepatotoxicant administration. Hepatic expression of the autophagosomal membrane protein LC3-II was significantly suppressed after CCl₄ administration by rapamycin pretreatment, compared with that in vehicle (DMSO) pretreatment. Expression of autophagy cargo protein p62, were significantly decreased after rapamycin treatment with AA administration. Hepatic p62 expression increased by chloroquine pretreatment. Serum AST and ALT were decreased after CCl₄ exposure in both rapamycin- and chloroquine-pretreated rats. On the other hand, regardless of pretreatment, pathological changes were mild in rats with AA exposure. These results showed that pretreatment with rapamycin or chloroquine can attenuate CCl₄-induced acute liver injury in rats.

Ectopic intestinal cysts are extremely rare in the rat liver. Here, we report a case of a spontaneous ectopic intestinal cyst in the liver of an 8‑week‑old male Crl:CD (SD) rat. Necropsy revealed a solitary white, firm nodule, approximately 3 mm in diameter on the diaphragmatic surface near the porta hepatis of the medial lobe of the liver. Histologically, the lesion exhibited a cystic structure lined with tissue resembling intestinal mucosa, located on the liver capsule. Periodic acid‑Schiff and Alcian blue (pH 1.0) staining‑positive mucous cells, similar to goblet cells, and Paneth cell‑like cells containing eosinophilic granules were observed in the mucosal epithelium. Immunohistochemically, the mucosal epithelium demonstrated low proliferative activity, as confirmed by Ki‑67 staining. The thin outer layer of the mucosa was positive for alpha‑smooth muscle actin, suggesting the presence of the lamina muscularis or a poorly developed muscular layer. Based on the lesion’s location and histological features, this case was diagnosed as an ectopic intestinal cyst, likely resulting from persistence of the vitelline duct. To the best of our knowledge, there are no previous reports of ectopic intestinal cysts in the rat liver that include such detailed histochemical and immunohistochemical findings. This report provides valuable insights into congenital lesions of the rat hepatobiliary system.