Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma.

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.

CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils.

Background: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy. Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively. Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs). Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

PCSK9: A emerging participant in heart failure.

Heart failure (HF) is a complex clinical syndrome caused by various cardiovascular diseases. Its main pathogenesis includes cardiomyocyte loss, myocardial energy metabolism disorder, and activation of cardiac inflammation. Due to the clinically unsatisfactory treatment of heart failure, different mechanisms need to be explored to provide new targets for the treatment of this disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene mainly related to familial hypercholesterolemia, was discovered in 2003. Aside from regulating lipid metabolism, PCSK9 may be involved in other biological processes such as apoptosis, autophagy, pyroptosis, inflammation, and tumor immunity and related to diabetes and neurodegenerative diseases. Recently, clinical data have shown that the circulating PCSK9 level is significantly increased in patients with heart failure, and it is related to the prognosis for heart failure. Furthermore, in animal models and patients with myocardial infarction, PCSK9 in the infarct margin area was also found to be significantly increased, which further suggested that PCSK9 might be closely related to heart failure. However, the specific mechanism of how PCSK9 participates in heart failure remains to be further explored. The purpose of this review is to summarize the potential mechanism of PCSK9's involvement in heart failure, thereby providing a new treatment strategy for heart failure.

Efficacy and safety of sofosbuvir/velpatasvir with or without ribavirin in hepatitis C genotype 3 compensated cirrhosis: A meta-analysis.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL) is an effective pan-genotypic direct-acting antiviral combination for treatment of chronic HCV infection. While the addition of ribavirin (RBV) to SOF/VEL improved sustained virological response (SVR12) in genotype 3 (GT3) decompensated cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear. AIM: To evaluate the efficacy and safety of SOF/VEL, with or without RBV in GT3 compensated cirrhosis patients. METHODS: We searched four electronic databases (PubMed/Medline, Embase, Cochrane Library and Web of Science) from inception up to June 2021 using both free text and MeSH terms. There was no restriction on language, geography, publication dates and publication status (full text or abstracts). All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL, with or without RBV, were included, regardless of age, gender or prior treatment experience. The primary outcome was sustained virological response 12-wk post-treatment (SVR12). The secondary outcome was treatment-related adverse events, as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL. The pooled relative risk (RR), 95%CI and heterogeneity (I 2) were estimated using Review Manager version 5.3. RESULTS: From 1752 citations, a total of seven studies (2 randomized controlled trials, 5 cohort studies) with 1088 subjects were identified. The SVR12 was similar in GT3 compensated cirrhosis patients, regardless of the use of RBV, for both the intention-to-treat RR 1.03, 95%CI: 0.99-1.07; I 2 = 0%) and the per-protocol analysis (RR: 1.03, 95%CI: 0.99-1.07; I 2 = 48%). The overall pooled rate of treatment-related adverse events was 7.2%. Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL (RR: 4.20, 95%CI: 1.29-13.68; I 2 = 0%). Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions. However, addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients. CONCLUSION: Ribavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL. Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.

An mALBI-Child-Pugh-based nomogram for predicting post-hepatectomy liver failure grade B-C in patients with huge hepatocellular carcinoma: a multi-institutional study.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is a severe complication in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. This study aims to develop a nomogram of PHLF grade B-C in patients with huge HCC (diameter ≥ 10 cm). METHODS: We retrospectively collected clinical information of 514 and 97 patients who underwent hepatectomy for huge HCC at two medical centers between 2016 and 2021. Univariate and multivariate analysis were carried out to screen the independent risk factors of PHLF grade B-C, which were visualized as a nomogram. RESULTS: Three Hundred Forty Three Thousand One Hundred Seventy One  and 97 HCC patients were included in the training cohort, internal validation cohort, and external validation cohort, with probabilities of PHLF grade B-C of 15.1%, 12.9%, and 22.7%, respectively. Pre-operative modified albumin-bilirubin (mALBI) grade (p < 0.001), Child-Pugh classification (p = 0.044), international normalized ratio (INR) (p = 0.005), cirrhosis (p = 0.019), and intraoperative blood loss (p = 0.004) were found to be independently associated with PHLF grade B-C in the training cohort. All the five independent factors were considered in the establishment of the nomogram model. In the internal validation cohort and external validation cohort, the area under receiver operating characteristic curve for the nomogram in PHLF grade B-C prediction reached 0.823 and 0.740, respectively. Divided into different risk groups according to the optimal cut-off value, patients in the high-risk group reported significantly higher frequency of PHLF grade B-C than those in the low-risk group, both in the training cohort and the validation cohort (p < 0.001). CONCLUSIONS: The proposed noninvasive nomogram based on mALBI-Child-Pugh and three other indicators achieved optimal prediction performance of PHLF grade B-C in patients with huge HCC.

Vildagliptin prevents cognitive deficits and neuronal apoptosis in a rat model of Alzheimer's disease.

Diabetes has been identified to be a risk factor for Alzheimer's disease (AD). Vildagliptin, a novel oral hypoglycemic agent, has been demonstrated to exert protective effects on the pancreas and cardiovascular system. The present study examined the potential protective effects of vildagliptin on neurons in an AD rat model. Treatment with vildagliptin improved memory deficits and decreased neuronal apoptosis in the hippocampus. The expression levels of B cell lymphoma 2 (Bcl­2) were increased, and the expression levels of caspase­3, Bcl­2 associated X protein and AD­associated proteins were decreased in the hippocampus following treatment with vildagliptin. Additionally, the AD model­induced decrease in phosphorylated (p) protein kinase B (p­Akt), p­glycogen synthase kinase 3ß (p­GSK3ß), post­synaptic density 95 and synaptophysin expression was reversed. These results indicate that vildagliptin administration exerts a protective effect against cognitive deficits by reducing tau phosphorylation and increasing the expression of proteins associated with synaptic plasticity in the hippocampus. Targeting of the Akt/GSK3ß signaling pathway may be a key mechanism in preventing the disease progression of AD.

Chemical composition and hypoglycemic and pancreas-protective effect of leaf essential oil from indigenous cinnamon (Cinnamomum osmophloeum Kanehira).

The antidiabetic effect of cinnamon has generated broad interest during the past decade. We investigated the hypoglycemic activity and pancreas-protective effect of leaf essential oil from indigenous cinnamon (CO) in diabetic rats induced with streptozotocin (STZ, iv, 65 mg/(kg bw)) and found linalool to be the major component representing 40.24% of the CO composition. In diabetics, all tested doses of CO significantly lowered fasting blood glucose and fructosamine and are concomitant with elevated plasma and pancreatic insulin levels under a fasting condition. However, during the oral glucose tolerance test (OGTT) period the effect of 25 and 50 mg/(kg bw) of CO was shown to be less effective than that of 12.5 mg/(kg bw) in ameliorating the accumulation of plasma insulin. In addition, at 12.5 mg/(kg bw), CO significantly ameliorated pancreatic values of thiobarbituric acid reactive substances and activities of superoxide dismutase and glutathione reductase in diabetics to an extent greater than that of higher CO doses. At doses 12.5 and 25 but not 50 mg/(kg bw), CO significantly ameliorated pancreatic levels of interleukin-1ß and nitric oxide. In conclusion, appropriate doses of CO of the linalool chemotype exhibited therapeutic potential in glycemic control in diabetes that was at least partially resulted from improved insulin secretion. The ameliorated oxidative stress and proinflammatory environment in the pancreas by CO may provide a protective effect on pancreatic ß cells and warrant further investigation.

[Differences in the expression of inhibin receptors and activin receptors in normal human ovaries and their significance].

OBJECTIVE: To explore the differences in the expression of inhibin (INH) receptors and activin (ACT) receptors in the follicular/luteinic phase in normal human ovaries and their relationship with female endocrine hormone levels. METHODS: Real time PCR and immunohistochemistry were used to determine the expression of inhibin receptors (INHR) genes, activin receptors (ACTR) genes. Serum estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), INHB, ACTA levels were determined by a solid quantitative sandwich enzyme immunoassay technique (Sandwich ELISA) in 21 women during follicular phase and another 21 women during luteinic phase, the correlations between each gene and each hormone were analyzed. RESULTS: (1) ACT type I and II receptors genes (ACTR I A, ACTR I B, ACTR II A, ACTR II B) and INH receptor beta-glycan genes were expressed higher in the follicular phase than in the luteinic phase: ACTR I A (0.50 +/- 0.17 vs 0.36 +/- 0.18; P < 0.05), ACTR I B (0.050 +/- 0.019 vs 0.036 +/- 0.020; P < 0.05), ACTR II A (0.10 +/- 0.04 vs 0.07 +/- 0.04; P < 0.05), ACTR II B (0.28 +/- 0.10 vs 0.19 +/- 0.11; P < 0.05), beta-glycan (0.26 +/- 0.10 vs 0.17 +/- 0.09; P < 0.01). (2) The intensities of ACTR I A, ACTR II A, beta-glycan immunostaining in human normal ovaries in the follicular phase were significantly stronger compared to those in luteinic phase. In the follicular phase beta-glycan expression was positively correlated with serum E2, FSH, LH, INHB levels. The correlation coefficient was 0.53 (P < 0.05), 0.74 (P < 0.01), 0.85 (P < 0.01) and 0.76 (P < 0.01) respectively. CONCLUSION: In normal human ovary in the follicular phase INH and ACT bind their receptors and down-regulate or up-regulate FSH, thus influencing the follicular development.