Ductular reaction is associated with liver disease progression, but there are no drugs targeting ductular reaction. Vitamin D deficiency is common in chronic liver diseases and related to disease progression, but the underlying mechanisms by which vitamin D regulates liver diseases progression remain unclear. Here, we show that vitamin D plasma levels are negatively correlated with the degree of ductular reaction in patients with chronic liver diseases. 1,25(OH)₂D_3, the active form of vitamin D, reduces 3,5-diethoxycarbonyl-1,4-dihydrocollidin (DDC)-induced ductular reaction, liver inflammation, and fibrosis in female mice and upregulates the vitamin D target gene, TXNIP (encoding thioredoxin-interacting protein), in ductular cells. Cholangiocyte-specific Txnip-knockout female mice are more susceptible to DDC-induced ductular reaction, inflammation, and fibrosis. Deletion of Txnip in cholangiocytes promotes proliferation and suppressed death. Furthermore, Txnip deficiency increases TNF-α and TGF-β secretion by cholangiocytes to stimulate Kupffer cells and hepatic stellate cells, consequently leading to inflammation and collagen deposition. Biliary Txnip deficiency abolishes the protective effects of vitamin D, and TXNIP overexpression attenuates DDC-induced ductular reaction and inflammation and fibrosis. Collectively, our findings identify new mechanism how vitamin D ameliorates liver diseases and suggest that the vitamin D/TXNIP axis is a therapeutic target for addressing ductular reaction and liver diseases.

Although drug-induced liver injury (DILI) is a major target of the pharmaceutical industry, we currently lack an efficient model for evaluating liver toxicity in the early stage of its development. Recent progress in artificial intelligence-based deep learning technology promises to improve the accuracy and robustness of current toxicity prediction models. Mask region-based CNN (Mask R-CNN) is a detection-based segmentation model that has been used for developing algorithms. In the present study, we applied a Mask R-CNN algorithm to detect and predict acute hepatic injury lesions induced by acetaminophen (APAP) in Sprague-Dawley rats. To accomplish this, we trained, validated, and tested the model for various hepatic lesions, including necrosis, inflammation, infiltration, and portal triad. We confirmed the model performance at the whole-slide image (WSI) level. The training, validating, and testing processes, which were performed using tile images, yielded an overall model accuracy of 96.44%. For confirmation, we compared the model’s predictions for 25 WSIs at 20× magnification with annotated lesion areas determined by an accredited toxicologic pathologist. In individual WSIs, the expert-annotated lesion areas of necrosis, inflammation, and infiltration tended to be comparable with the values predicted by the algorithm. The overall predictions showed a high correlation with the annotated area. The R square values were 0.9953, 0.9610, and 0.9445 for necrosis, inflammation plus infiltration, and portal triad, respectively. The present study shows that the Mask R-CNN algorithm is a useful tool for detecting and predicting hepatic lesions in non-clinical studies. This new algorithm might be widely useful for predicting liver lesions in non-clinical and clinical settings.

Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological condition affecting elderly men. Prunella vulgaris L. (PV), a perennial herbaceous plant native to Europe and Asia, has anti-inflammatory, antioxidant, and antimicrobial effects. In this study, we determined the effect of PV extract on the development of BPH. Methods: Rats were treated via a daily hypodermic injection of testosterone propionate (TP; 3 mg/kg) for 4 weeks. Groups of BPH rats were treated with or without PV (60 or 80 mg/kg) by oral gavage. Results: In BPH model rats, PV considerably reduced their relative prostate weight and serum concentrations of dihydrotestosterone (DHT) and testosterone. The TP-induced increases in epithelial thickness in the prostate, proliferating cell nuclear antigen (PCNA) expression, and cyclin D1 expression were remarkably reduced, whereas terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells and cleaved caspase-3 levels were increased, in PV-treated rats compared to BPH rats. The mRNA expression levels of growth factors, such as transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), and insulin-like growth factor (IGF-2), were significantly reduced in PV-treated rats. Mechanistically, the TP-induced activation of c-Jun N-terminal kinase (JNK) was reduced by PV administration. Conclusions: These results designate that PV effectively ameliorates the development of testosterone-induced BPH through anti-androgenic, anti-proliferative, and pro-apoptotic activities, suggesting that it could be a potential therapeutic substance for BPH.

Kim HJ, et al. Korean J Physiol Pharmacol. 2018 Nov;22(6):713-719. https://doi.org/10.4196/kjpp.2018.22.6.713

Jakyakgamcho-tang (JGT) is used in oriental medicine to treat inflammation and allergy. Chronic obstructive pulmonary disease (COPD) causes respiratory inflammation, airway remodeling, and pulmonary emphysema. We examine the influence of JGT on COPD by using a mouse model. COPD was induced by inhalation of cigarette smoke (CS) and nasal administration of lipopolysaccharide (LPS). In comparison to COPD mice induced by CS and LPS, mice administered with JGT exhibited significantly lower amounts of inflammatory cells and reduced expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) and lung tissue. The elevated concentrations of transforming growth factor-β (TGF-β), α-smooth muscle actin (α-SMA), and matrix metallopeptidase-9 (MMP-9) induced by CS and LPS were also inhibited by JGT treatment. Moreover, JGT suppressed CS and LPS-induced phosphorylation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase1/2 (ERK1/2) and mitogen-activated protein kinases (p38 MAPKs). In a COPD mouse model, our results demonstrated that JGT prevented CS and LPS induced airway inflammation and remodeling.

Benign prostatic hyperplasia (BPH) is a common disease in aging men. Panicum dichotomiflorum (PD) is an annual grass species of Poaceae that is distributed worldwide. The present study examined whether PD has a protective effect against BPH. BPH was generated in rats by daily subcutaneous administration of testosterone for four weeks. During this period, the rats were also given daily oral gavages of an extract of PD (150 mg/kg). After the final treatment, all animals were euthanized and their prostates were collected and weighed. In BPH model rats, the prostate weight and levels of dihydrotestosterone (DHT) and 5α-reductase expression were inhibited following treatment with PD extract. Testosterone-induced increases in prostate gland epithelial thickness and expression of cyclin D1 and proliferating cell nuclear antigen (PCNA) were markedly suppressed in PD-treated rats, whereas cleaved caspase-3 levels were increased. PD administration also decreased the expression of transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF), the phosphorylation of Akt, and inflammatory cytokines levels. Taken together, these results show that PD extract protects against testosterone-induced BPH progression by alleviating prostate cell growth and reducing levels of growth factors and inflammatory cytokines, indicating that PD extract may have potential in protecting against BPH.