Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis.

The interplay between hepatocellular carcinoma (HCC) cells and the tumor microenvironment is essential for hepatocarcinogenesis, but their contributions to HCC development are incompletely understood. We assessed the role of ANGPTL8, a protein secreted by HCC cells, in hepatocarcinogenesis and the mechanisms through which ANGPTL8 mediates crosstalk between HCC cells and tumor-associated macrophages. Immunohistochemical, Western blotting, RNA-Seq, and flow cytometry analyses of ANGPTL8 were performed. A series of in vitro and in vivo experiments were conducted to reveal the role of ANGPTL8 in the progression of HCC. ANGPTL8 expression was positively correlated with tumor malignancy in HCC, and high ANGPTL8 expression was associated with poor overall survival (OS) and disease-free survival (DFS). ANGPTL8 promoted HCC cell proliferation in vitro and in vivo, and ANGPTL8 KO inhibited the development of HCC in both DEN-induced and DEN-plus-CCL4-induced mouse HCC tumors. Mechanistically, the ANGPTL8-LILRB2/PIRB interaction promoted polarization of macrophages to the immunosuppressive M2 phenotype in macrophages and recruited immunosuppressive T cells. In hepatocytes, ANGPTL8-mediated stimulation of LILRB2/PIRB regulated the ROS/ERK pathway and upregulated autophagy, leading to the proliferation of HCC cells. Our data support the notion that ANGPTL8 has a dual role in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis.

Boosting Glioblastoma Therapy with Targeted Pyroptosis Induction.

Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe-emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis-mediated GBM therapy. However, administering AE is challenging due to the blood-brain barrier (BBB) and its non-selectivity. To overcome this obstacle, AE@ZIF-8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol-poly (lactic-co-glycolic acid) (PEG-PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE-NPs (Tf-PEG-PLGA modified AE@ZIF-8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE-NPs activate antitumor immunity and reduce AE-related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity.

ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways.

INTRODUCTION: High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood. OBJECTIVES: This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation. METHODS: The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression. RESULTS: ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo. CONCLUSIONS: Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.

ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition.

Background: Ectopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported. Methods: We used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/ß-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3ß inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8. Results: ANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/ß-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression. Conclusions: ANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.

ANGPTL8 is a negative regulator in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3ß activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3ß activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.

Retracted: Serum 25-hydroxyvitamin D and risk of type 2 diabetes in older adults: A dose-response meta-analysis of prospective cohort studies.

Lower serum level of 25-hydroxyvitamin D is common in older adults and associated with several negative outcomes. However, previous studies have indicated that 25-hydroxyvitamin D is associated with risk of type 2 diabetes, but presented controversial results.Studies in PubMed and EMBASE were searched update to June 2017 to identify and quantify the potential dose-response association between low 25-hydroxyvitamin D and risk of type 2 diabetes in older adults.Nine eligible studies involving a total of 34,511 participants with 2863 incident cases were included in this meta-analysis. Our results showed statistically significant association between lower 25-hydroxyvitamin D and type 2 diabetes in older adults [odds ratio (OR) = 1.19, 95% confidence interval (95% CI): 1.08-1.32, P = .001]. In addition, we obtained the best fit at an inflection point of decrease 10 ng/mL in piecewise regression analysis; the summary relative risk of type 2 diabetes in older adults for a decrease of 10 ng/mL 25-hydroxyvitamin D was 1.06 (95% CI: 1.02-1.13, P < .001). Furthermore, subgroups analysis indicated that lower 25-hydroxyvitamin D was associated with a significant increment risk of type 2 diabetes in older adults in female (OR = 1.21, 95% CI: 1.04-1.40, P = .014) but not in male (OR = 1.11, 95% CI: 0.75-1.63, P = .615). Subgroup meta-analyses in study design, duration of follow-up, number of participants, and number of cases showed consistent with the primary findings.Lower 25-hydroxyvitamin D is associated with type 2 diabetes in older adults risk increment.