Avicularin alleviates acute liver failure by regulation of the TLR4/MyD88/NF-κB and Nrf2/HO-1/GPX4 pathways to reduce inflammation and ferroptosis.

Acute liver failure (ALF) is an inflammation-mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti-inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS-stimulated RAW 264.7 cells via blocking the toll-like receptor 4 (TLR4)/myeloid differentiation protein-88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. Moreover, AL attenuated ferroptosis in D-GalN-induced HepG2 cells by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D-GalN-induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF-κB pathway and activating Nrf2/HO-1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.

Higher serum uric acid to HDL-cholesterol ratio is associated with onset of non-alcoholic fatty liver disease in a non-obese Chinese population with normal blood lipid levels.

BACKGROUND: Recent studies have demonstrated the presence of associations between metabolic syndrome and the onset of nonalcoholic fatty liver disease (NAFLD). Metabolic syndrome, in turn, has been found to be linked to high serum uric acid to HDL-cholesterol ratios (UHR). However, the relationship between UHR values and the occurrence of NAFLD in non-obese individuals remains unknown. The present study aimed to examine the possible correlation between UHR values and NAFLD onset among a non-obese Chinese population without dyslipidemia, as well as comparing the predictive value of UHR versus other NAFLD onset predictors. METHODS: A total of 9837 non-obese patients, with normal blood lipid levels, were included in a 5-year retrospective cohort study, and the onset of NAFLD in these patients was diagnosed by liver ultrasound. RESULTS: Out of the 9837 patients, 855 were diagnosed with NAFLD during the 5-year follow-up period, for an overall total prevalence of 8.7% at the end of the study period. Across quintiles 1, 2, 3, 4 and 5 of UHR (respectively, ratios of ≤ 120.88, 120.89-154.01, 154.02-189.91, 189.92-240.46, and ≥ 240.47), the prevalence of NAFLD among the patients increased from 2.4%, 5%, 7.9%, 10.3%, and 17.8%, respectively. After adjustments for age, gender, liver and kidney functional markers, as well as metabolic indicators, multivariate Cox proportional hazard regression analysis demonstrated that the hazard ratio (HR) was the highest in quintile 5, at 1.76 (1.12-2.75), and the lowest in quintile 1. The area under the curve (AUC) for UHR (0.690) was higher than that for serum uric acid (UA, 0.666) and HDL-C (0.636), suggesting the predictive ability of UHR for NAFLD onset was better than either alone. This finding was further supported by the presence of an independent association between UHR and NAFLD, even within the normal range of UA and HDL-C; the HR (95% confidence interval, CI) for NAFLD was 1.002 (1.000-1.004). Compared with other significant predictors, AUC for UHR (0.67) was similar to that of low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C, 0.68), non-high-density lipoprotein cholesterol (NHDL-C)/HDL-C (0.68) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratios (0.7), and was higher than that of LDL-C (0.63), remnant cholesterol (RC,0.59), and albumin (ALB)/alkaline phosphatase (ALP) ratio (0.61). The sensitivity of UHR (71%) was the highest among all indicators. In the subgroup with ALT < 40U/L, the AUC for UHR was 0.70, which was the highest among all predictors; among ALT > 40U/L, UHR was able to predict the occurrence of NAFLD (AUC = 0.61, p = 0.007), which was not the case for RC (P = 0.441), ALB/ALP (P = 0.419), and ALT/AST (P = 0.159). CONCLUSIONS: UHR serve as an inexpensive and reliable predictor of NAFLD onset in non-obese Chinese people with normal blood lipid levels, allowing for identification of individuals at high risk for NAFLD.

The effects of granulocyte-colony stimulating factor on chronic liver disease: a meta-analysis.

INTRODUCTION: The clinical application of granulocyte-colony stimulating factor on chronic liver disease is still controversial. The study aimed to evaluate the effects of granulocyte-colony stimulating factor on chronic liver disease. METHODOLOGY: A systematic literature search was performed in PubMed, Embase, Cochrane Library and Chinese Biomedical Literature database. Randomized-controlled trials assessing the efficacy of granulocyte-colony stimulating factor were selected. RESULTS: Granulocyte-colony stimulating factor was associated with an increasing long-term survival (RR 1.54; 95% CI 1.22 to 1.94; p = 0.0003; heterogeneity: Q = 0.26, I2 = 25%) and an increasing short-term survival (RR 1.44; 95% CI 1.16 to 1.78; p = 0.0009; heterogeneity: Q < 0.00001, I2 = 80%). Granulocyte-colony stimulating factor failed to lower mortality secondary to multiple organ failure (RR 0.65; 95% CI 0.34 to 1.21; p = 0.17; heterogeneity: Q = 0.45; I2 = 0%), gastrointestinal bleeding mortality (RR 0.97; 95% CI 0.61 to 1.56; p = 0.91; heterogeneity: Q = 0.35; I2 = 11%) and sepsis mortality (RR 0.27; 95% CI 0.06 to 1.12; p = 0.07; heterogeneity: Q < 0.00001; I2 = 90%). It significantly lowered the Child-Turcotte-Pugh (MD=-0.97, 95% CI -1.48 to -0.45; p = 0.0003; heterogeneity: Q = 0.25; I2 = 28%). No serious adverse events were observed. CONCLUSIONS: Granulocyte-colony stimulating factor resulted in significantly improved 12-month survival and reduced Child-Turcotte-Pugh score with relative safety. Establishment of guidelines and protocols in future clinical trials will promote granulocyte-colony stimulating factor as an effective and safe therapy for chronic liver disease.