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.

Alpha-synuclein (αSyn) species, especially the oligomers and fibers, are associated with multiple neurodegenerative diseases and cannot be directly targeted under the conventional pharmacological paradigm. Proteolysistargeting chimera technology confers degradation of various "undruggable" targets; however, hardly any small-molecule degrader for αSyn aggregates has been reported yet. Herein, by using the probe molecule sery308 as a warhead, a series of small-molecule degraders for αSyn aggregates were designed and synthesized. Their degradation effects on αSyn aggregates were evaluated on a modified pre-formed fibril-seeding cell model. Compound 2b exhibited the highest degradation efficiency (DC 50 = 7.51 ± 0.53 μM) with high selectivity. Mechanistic exploration revealed that both proteasomal and lysosomal pathways were involved in this kind of degradation. Moreover, the therapeutic effects of 2b were tested on SH-SY5Y (human neuroblastoma cell line) cells and Caenorhabditis elegans. Our results provided a new class of small-molecule candidates against synucleinopathies and broadened the substrate spectrum of PROTAC-based degraders.

Nonalcoholic fatty liver disease (NAFLD) represents a class of disorders including hepatic steatosis, steatohepatitis, and liver fibrosis. Previous research suggested that xyloketal B (Xyl-B), a marine-derived natural product, could attenuate the NAFLD-related lipid accumulation. Herein, we investigated the protective mechanism of Xyl-B in a high-fat diet (HFD) mice fatty liver model by combining a quantitative proteomic approach with experimental methods. The results showed that the administration of Xyl-B (20 and 40 mg• kg −1 •day −1 , ip) ameliorated the hepatic steatosis in HFD mice. Proteomic profiling together with bioinformatics analysis highlighted the upregulation of a cluster of peroxisome proliferator-activated receptor-α (PPARα) downstream enzymes mainly related to fatty acid oxidation (FAO) as key changes after the treatment. These changes were subsequently confirmed by bioassays. Moreover, further results showed that the expression levels of PPARα and PPARγ coactivator-1α (PGC1α) were increased after the treatment. The related mode-of-action was confirmed by PPARα inhibition. Furthermore, we evaluated the PPARαmediated anti-inflammatory and antifibrosis effect of Xyl-B in methionine-choline-deficient (MCD) mice hepatitis and liver fibrosis models. According to the results, the histological features were improved, and the levels of inflammatory factors, adhesion molecules, as well as fibrosis markers were decreased after the treatment. Collectively, these results indicated that Xyl-B ameliorated different phases of NAFLD through activation of the PPARα/PGC1α signaling pathway. Our findings revealed the possible metabolism-regulating mechanism of Xyl-B, broadened the application of xyloketal family compounds, and may provide a new strategy to curb the development of NAFLD.

Background Non-alcoholic fatty liver disease (NAFLD) has been associated with type 2 diabetes, but its relationship with pre-diabetes is still unknown. This study aims to determine whether pre-diabetes is associated with NAFLD, followed by establishing a NAFLD predictive nomogram for lean Chinese pre-diabetics with normal blood lipids. Methods Datasets from 3 previous studies, 1 (2774 pre-diabetics with normal blood lipids for training, 925 for validation), 2 (546 for longitudinal internal validation, post-5-year follow-up), and 3 (501 from another institution for external validation), were used. Kaplan-Meier determined cumulative NAFLD hazard, and least absolute shrinkage and selection operator regression analysis uncovered its risk factors. Multivariate logistic regression analysis constructed the nomogram, followed by validation with receiver operating characteristic curve, calibration plot, and decision curve analyses. Results NAFLD incidence increased with diabetes progression, and pre-diabetics had higher cumulative risk versus non-diabetics, even for lean individuals with normal blood lipids. Six risk factors were identified: body mass index, total cholesterol, alanine aminotransferase:aspartate aminotransferase, triglyceride:high density lipoprotein cholesterol, fasting blood glucose and γ-glutamyl-transferase. The nomogram yielded areas under the curve of 0.808, 0.785, 0.796 and 0.832, for respectively, training, validation, longitudinal internal validation, and external validation, which, along with calibration curve values of p = 0.794, 0.875, 0.854 and 0.810 for those 4 datasets and decision curve analyses, validated its clinical utility. Conclusions Lean pre-diabetic Chinese with normal blood lipids have higher NAFLD risk versus non-diabetics. The nomogram is able to predict NAFLD among such individuals, with high discrimination, enabling its use for early detection and intervention.

Background The purpose of this study was to compare the diagnostic value of serum oligosaccharide chain (G-test), alpha-fetoprotein (AFP) and aspartic aminotransferase to alanine aminotransferase ratios (AAR), both alone and in combination, for predicting hepatocellular carcinoma (HCC) onset. Methods Between Januarys 2020–2022, 152 subjects admitted to the First Affiliated Hospital of Nanchang University was enrolled in this study, of which 77 had HCC, 18 chronic hepatitis (CH), 37 liver cirrhosis (LC) and 20 were healthy. Data for patient characteristics were collected, and differences between groups were analyzed by either Mann-Whitney U or χ2 tests. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of AFP, G-test, and AAR for HCC. Results G-test, AFP, and AAR were all found to have close correlations with HCC among the different patient groups, with G-test being the most predictive for HCC among healthy and CL patients, as represented by respective areas under the curve (AUC) of 0.953 and 0.792 (P < 0.001). By contrast, AAR had the greatest diagnostic ability for HCC among CH patients (AUC = 0.850; P < 0.001). However, the combination of all 3 biomarkers obtained the most optimal results for predicting HCC onset, in terms of predictive capability for all 3 non-HCC patient groups, yielding AUCs of 0.958, 0.898, and 0.808 (P < 0.001) for, respectively, healthy, CH, and LC patients. Additionally, AFP had higher specificity, but lower sensitivity, with increased threshold values, as the recommended threshold of AFP ≥ 400 ng/mL yielded a missed diagnosis rate of 72.7%. For AFP-negative HCC (AFP-NHCC) patients, G-test alone had the greatest diagnostic capability (AUC = 0.855; P < 0.001), sensitivity (83.8%), and specificity (87.5%). Conclusion G-test has the greatest diagnostic capability for HCC and AFP-NHCC, with high sensitivity and specificity, among healthy and LC patients. However, AAR had the highest diagnostic capability and sensitivity for HCC in CH. Overall, though, the combination of G-test, AFP and AAR provided the most optimal outcomes for predicting HCC onset, no matter the patient pre-conditions.