Blocking the E2F transcription factor 1/high-mobility group box 2 pathway enhances the intervention effects of α-santalol on the malignant behaviors of liver cancer cells.

In view of the tumor-inhibiting effect of α-santalol in various cancers and the role of E2F transcription factor 1 (E2F1) as an important target for anticancer research, this study investigates the relation between α-santalol and E2F1, as well as the effect of α-santalol on liver cancer progression and the corresponding mechanism. Concretely, liver cancer cells were treated with different concentrations of α-santalol. The IC50 value of α-santalol was determined using Probit regression analysis. Then, transcription factors that are targeted by α-santalol and differentially expressed in liver cancer were screened out. The clinicopathological impact of E2F1 and its targets were evaluated and predicted. The expressions of E2F1 and high-mobility group box 2 (HMGB2) and their correlation in the liver cancer tissues were analyzed by bioinformatics. The effects of E2F1 and HMGB2 on the biological characteristics of liver cancer cells were examined through loss/gain-of-function and molecular assays. With the extension of treatment time, the inhibitory effects of 10 µmol/L and 20 µmol/L α-santalol on cancer cell survival rate were enhanced (P < 0.001). E2F1 and HMGB2 were highly expressed and positively correlated in liver cancer tissues (P < 0.05). High E2F1 expression was correlated with large tumors and high TNM stages (P < 0.05). E2F1 knockdown promoted the effects of α-santalol on dose-dependently inhibiting viability, colony formation, invasion and migration (P < 0.05). Moreover, E2F1 knockdown reduced the IC50 value and HMGB2 level, while HMGB2 overexpression produced opposite effects. HMGB2 overexpression and E2F1 knockdown mutually counteracted their effects on the IC50 value and on the viability and apoptosis of α-santalol-treated liver cancer cells (P < 0.01). Collectively, blocking the E2F1/HMGB2 pathway enhances the intervention effects of α-santalol on the proliferation, migration and invasion of liver cancer cells.

Endoplasmic reticulum stress inhibitor may substitute for sleeve gastrectomy to alleviate metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming the most common form of chronic liver disease worldwide. We explored the potential mechanisms responsible for the protective role of sleeve gastrectomy (SG) on MASLD in a high-fat diet (HFD) rat model. METHODS: Rats were fed with HFD for 12 weeks to generate MASLD model that were subjected to SG or sham surgery. The endoplasmic reticulum stress (ERS) inhibitor 4-phenylbutyric acid (4-PBA) was injected intraperitoneally every day for 4 weeks after surgery to identify the impact of ERS. RESULTS: The MASLD rat model was generated successfully, as indicated by significant upregulation of metabolic parameters. Fibroblast growth factor 21 (FGF21) and ERS-related proteins were increased in HFD rats, while expression of fibroblast growth factor receptor 1 was decreased as expected. An HFD also induced swelling and blurring of the endoplasmic reticulum and mitochondria in hepatocytes, and the above transformation could be relieved by SG and 4-PBA. SG and an ERS inhibitor both inhibited MASLD, but their combined treatment had no additional benefit. CONCLUSIONS: Dysfunction of the FGF21 signaling pathway and hepatic steatosis and inflammation could be induced by an HFD, potentially causing MASLD. Bariatric surgery and ERS inhibition could alleviate MASLD by relieving ERS-mediated impairment of FGF21 signal transduction. These findings provide a new insight into the use of ERS inhibitors to treat MASLD, especially in patients who prefer to avoid surgery.

Effects of Left Gastric Artery Ligation Versus Sleeve Gastrectomy on Obesity-Induced Adipose Tissue Macrophage Infiltration and Inflammation in Diet-Induced Obese Rats.

BACKGROUND Bariatric procedures such as left gastric artery ligation (LGAL) and sleeve gastrectomy (SG) have emerged as important procedures for treating morbid obesity. In this study, we compared the effects of LGAL vs. SG on obesity-induced adipose tissue macrophage infiltration and inflammation in diet-induced obese rats. MATERIAL AND METHODS Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 16 weeks to induce obesity. SG, GLAL, or corresponding sham surgeries were performed in anesthetized rats. Inflammatory factor expression in serum and epididymal and retroperitoneal adipose tissues were analyzed 4 weeks after surgery. Macrophage infiltration and phenotype transformation were also assessed with Western blot analysis and immunofluorescence. RESULTS Both LGAL and SG strongly attenuated high-fat diet (HFD)-induced fat accumulation in retroperitoneal and epididymal tissues. The expressions of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 were downregulated after LGAL and after SG by promoting activation of M2 macrophages, despite continued exposure to HFD. Furthermore, both LGAL and SG resulted in increased macrophage infiltration, but did not contribute to phenotype transformation of macrophages to M1. CONCLUSIONS LGAL and SG both reduced fat accumulation caused by HFD feeding. Therapies designed to ameliorate the inflammatory response by promoting activation of M2 macrophages may be valuable.

Sleeve gastrectomy attenuates high fat diet-induced non-alcoholic fatty liver disease.

BACKGROUND: A high-fat diet (HFD) is known to lead to obesity, and contributes to the progression of non-alcoholic fatty liver disease. The objective of this study was to evaluate the effects of sleeve gastrectomy (SG) on the progression of HFD-induced hepatic steatosis. METHODS: Fifteen 4-week-old, male Wistar rats were randomly assigned into three groups: NC, HFD + SHAM and HFD + SG. Their body weight, glucose-lipid metabolism, inflammation indices, hepatic steatosis and fibroblast growth factor 21 (FGF21) levels were measured. RESULTS: Postoperatively, body weights in the HFD + SHAM and HFD + SG group rats decreased during the first week. Thereafter, HFD + SG rats regained their body weight. Differences in insulin, homeostasis model assessment of insulin resistance, triglyceride, free fatty acid, tumor necrosis factor-α and monocyte chemotactic protein-1 levels were statistically significant across the three groups (all P < 0.05). Interestingly, FGF21 levels in the HFD + SG group were markedly lower than in the HFD + SHAM group (P = 0.015), however, there were no differences in the NC group. Hematoxylin and eosin staining demonstrated that more vacuoles were present in the HFD + SHAM liver when compared to the HFD + SG liver. Oil-red O staining showed less red dots in the HFD + SG liver. CONCLUSIONS: Despite eating, surgical re-routing of the gut may prevent weight accumulation, regulate glucose-lipid metabolism and insulin sensitivity, control a chronic inflammatory state, change the secretion pattern of FGF21 and alleviate the severity of fatty liver.

Tripterine treatment improves endothelial progenitor cell function via integrin-linked kinase.

BACKGROUND/AIMS: Atherosclerosis is associated with dysfunction of endothelial progenitor cells (EPCs). Tripterine, a chemical compound derived from the Chinese medicinal plant Tripterygium wilfordii Hook, displays anti-inflammatory properties in several animal models. We hypothesized that tripterine can improve EPC function and thus the efficiency of EPC transplantation. METHODS AND RESULTS: Tripterine preconditioning (2.5 µM, 4 h) improved EPC proliferation, tube formation, migration, and adhesion, and reduced apoptosis in cells cultured in ox-LDL (200 µg/ml). Tripterine restored integrin-linked kinase (ILK) levels downregulated by ox-LDL in EPCs, suggesting the involvement of the ILK/Akt pathway. Small interfering RNA-mediated depletion of ILK and dominant-negative ILK transduction inhibited the phosphorylation of the ILK downstream signaling targets protein kinase B/Akt and glycogen synthase kinase 3-beta (GSK-3ß), and reduced ß-catenin and cyclin D1 expression. In atherosclerotic mice injected with green fluorescent protein-labeled EPCs to evaluate EPC function, tripterine decreased aortic lesions and plaque deposition, and injection of tripterine-treated EPCs restored ILK levels. CONCLUSION: The present results suggest that tripterine improves vascular function in atherosclerosis by enhancing EPC function through a mechanism involving the ILK signaling pathway.

Genotype-Guided Dosing of Coumarin Anticoagulants: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Coumarin anticoagulants (acenocoumarol, phenprocoumon, and warfarin) are generally used for the prevention of stroke in patients with atrial fibrillation or for the therapy and prevention of venous thromboembolism. However, the safe use of coumarin anticoagulants is restricted by a narrow therapeutic window and large interindividual dosing variations. Some studies found that the effectiveness and safety of coumarin anticoagulants therapy were increased by pharmacogenetic-guided dosing algorithms, while others found no significant effect of genotype-guided therapy. METHODS: Four electronic databases were searched from January 1, 2000, to March 1, 2014, for randomized controlled trials of patients who received coumarin anticoagulants according to genotype-guided dosing algorithms. The primary outcome was the percentage of time that the international normalized ratio (INR) was within the normal range (2.0-3.0). Secondary outcomes included major bleeding events, thromboembolic events, and INR ≥4 events. RESULTS: Eight studies satisfied the inclusion and exclusion criteria. Genotype-guided dosing of coumarin anticoagulants improved the percentage of time within the therapeutic INR range (95% confidence interval [CI], 0.02-0.28; P = .02; I(2) = 70%). Subgroup analysis was performed after dividing the nongenotype-guided group into a standard-dose group (95% CI, 0.14-0.49; P = .0004; I(2) = 50%) and a clinical variables-guided dosing algorithm group (95% CI, -0.07-0.15; P = .48; I(2) = 34%). There is a statistically significant reduction in numbers of secondary outcomes (INR ≥4 events, major bleeding events, and thromboembolic events; 95% CI, 0.79-1.00; P = .04). Subgroup analysis of secondary outcomes showed no significant difference between genotype-guided dosing and clinical variables-guided dosing (95% CI, 0.84-1.10; P = .57; I(2) = 11%), but genotype-guided dosing reduced secondary outcomes compared with standard dosing (95% CI, 0.62-0.92; P = .006; I(2) = 0%). CONCLUSIONS: This meta-analysis showed that genotype-guided dosing increased the effectiveness and safety of coumarin therapy compared with standard dosing but did not have advantages compared with clinical variables-guided dosing.

Short time tripterine treatment enhances endothelial progenitor cell function via heat shock protein 32.

The dysfunction of endothelial progenitor cells (EPCs) limits their potential for the treatment of ischemia and atherosclerosis. Therefore, we investigated the effect of tripterine on EPC function and examined the underlying mechanisms. The effect of tripterine, an active component of Tripterygium wilfordii Hook, on the enhancement of EPC function and the efficiency of EPC transplantation was investigated in vitro and in vivo. Treatment of EPCs with tripterine at 2.5 µM for 4 h inhibited oxidized low-density lipoprotein (ox-LDL) induced ROS production, cell apoptosis, and cell senescence and improved the migration and tube formation capacities of EPCs treated with ox-LDL (200 µg/ml). In vivo studies showed that tripterine conditioning of EPCs administered to ischemic foci improved blood perfusion and microvascular density in a mouse hindlimb ischemia model. Examination of the underlying mechanisms indicated that the effect of tripterine is mediated by the induction of heat shock protein 32 expression and the inhibition of JNK activation. The present results are of clinical significance because they suggest the potential of tripterine as a therapeutic agent to improve the efficacy of EPC transplantation for the treatment of ischemic diseases.

Effects of lipids and lipoproteins on diabetic foot in people with type 2 diabetes mellitus: a meta-analysis.

BACKGROUND: To conduct a meta-analysis of case-control studies to determine the effects of lipids and lipoproteins on morbidity of diabetic foot in adults with type 2 diabetes. METHODS: We searched the PubMed and EMBASE to identify eligible studies. The Newcastle-Ottawa Quality Assessment Scale was used to determine the quality of selected studies. We assessed the strength of associations using standardized mean differences with 95% confidence intervals. RESULTS: A total of 4 articles were found. Decreased HDL-cholesterol had a significant association with diabetic foot susceptibility in fixed-effects model, but no significant associations were found between diabetic foot and LDL-cholesterol, TC or TG levels. CONCLUSIONS: Our results suggested that decreased HDL-cholesterol was associated with diabetic foot, so possible measures to prevent diabetic foot should include targeting increases in HDL-cholesterol.