Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.

1. Numerous tacrolimus population pharmacokinetic (PPK) models in pediatric liver transplantation patients have been established to define an optimal dose schedule. However, the applicability of extrapolating these PPK models to our clinical center remains unknown. The goals of the present study was to evaluate model external predictiveness and establish a new model applicable to traditional therapeutic drug monitoring (TDM) data. 2. Published PPK models were collected from the literature and assessed using our real-world dataset including 41 pediatric liver transplantation patients via the individual prediction error method. The establishment of a new model was characterized using non-linear mixed-effects modeling (NONMEM). 3. Nine published pediatric liver transplantation PPK models were identified, three of which could be applied to our real-world dataset. However, these models were dissatisfactory in terms of individual prediction error and hence, inadequate for extrapolation. Finally, a new model applicable to our real-world dataset was established as follows: CL/F = 22.9×(WT/70)^0.75×(1 − WZ ×0.264)×(1 − FCZ ×0.338)×(1 + ASPI ×0.281)×(POD/41)^0.0486 L/h; V/F = 906×(WT/70) L. Where WT, WZ, FCZ, ASPI and POD were weight, wuzhi capsule, fluconazole, aspirin, and post-transplantation day, respectively. In conclusion, published models were inadequate for application to our real-world dataset. The present study produced a new model applicable to our real-world study data.

Astragaloside IV (AST) is the major active saponin in Astragalus membranaceus and, reportedly, has a variety of pharmacological activities. However, the potential of AST to ameliorate high glucose‑mediated renal tubular epithelial‑mesenchymal transition (EMT) remains undetermined. The aim of the present research was to explore the effect and mechanism of AST in EMT of renal tubular epithelial cells, as an underlying mechanism of renal fibrosis and a vital feature involved in diabetic nephropathy. The effect of AST on the EMT of renal tubular epithelial cells (HK‑2) stimulated by high glucose was investigated and it was attempted to elucidate the potential underlying mechanism. The expression of E‑cadherin and α‑smooth muscle actin were determined by western blotting and immunofluorescence assays. The expression of the mammalian target of rapamycin complex 1 (mTORC1)/ ribosomal protein S6 kinase β‑1 (p70S6K) signaling pathway and protein levels of four transcriptional factors (snail, slug, twist and zinc finger E‑box‑binding homeobox 1) were also determined by western blotting. Additionally, extracellular matrix components, including fibronectin (FN) and collagen type IV (Col IV) were detected by ELISA. The results suggested that the EMT of HK‑2 cells and the mTORC1/p70S6K pathway were activated by high glucose. The expression of snail and twist in HK‑2 cells was elevated by high glucose. Furthermore, extracellular matrix components, FN and Col IV, were increased in HK‑2 cells cultured with high glucose. In turn, treatment with AST reduced EMT features in HK‑2 cells, inhibited mTORC1/p70S6K pathway activation, downregulated expression of snail and twist, and reduced secretion of FN and Col IV. In summary, the findings suggested that AST ameliorates high glucose‑mediated renal tubular EMT by blocking the mTORC1/p70S6K signaling pathway in HK‑2 cells.

1. Several tacrolimus population pharmacokinetic (PPK) models in hematopoietic stem cell transplantation (HSCT) patients have been set up to recommend an optimal dosage schedule. However, the PPK model of Chinese pediatric HSCT patients has not been reported. The study is to investigate whether published PPK models of HSCT patients can be used to simulate Chinese pediatric HSCT patients and establish the tacrolimus PPK model of Chinese pediatric HSCT patients. 2. Published PPK models were collected from the literature and assessed using Chinese pediatric HSCT patients via the individual prediction error method. The establishment of tacrolimus PPK model in Chinese pediatric HSCT patients were characterized with nonlinear mixed-effects modeling (NONMEM). 3. Three published HSCT PPK models were identified, two of which could be applied to our external dataset. However, these models were dissatisfactory in terms of individual prediction error and hence, inadequate for extrapolation. Finally, a new tacrolimus PPK model in Chinese pediatric HSCT patients was established. Based on the simulation results of our model, new initial dosage suggestions were recommendated. In conclusion, the tacrolimus PPK model in Chinese pediatric HSCT patients was presented and the model could be used to predict individualized dosing regimens in children with HSCT.

The present study aimed to investigate the effects of metformin on body weight in polycystic ovary syndrome (PCOS) patients by model-based meta-analysis (MBMA). Randomized controlled trial (RCT) st...