ABSTRACT
BACKGROUND AND AIMS: Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. METHODS: Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1-/-) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. RESULTS: CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1-/- mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. CONCLUSIONS: Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH.
Subject(s)
Non-alcoholic Fatty Liver Disease , Phenylurea Compounds , Piperidines , Animals , Humans , Mice , Choline/metabolism , Choline/pharmacology , Disease Models, Animal , Liver/metabolism , Liver Cirrhosis/pathology , Macrophage Activation , Mechanistic Target of Rapamycin Complex 1/metabolism , Methionine/metabolism , Methionine/pharmacology , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolism , Receptors, CCR1/genetics , Receptors, CCR1/metabolism , Receptors, Chemokine/metabolismABSTRACT
Objective: The objective of this study was to observe and analyze changes in serum levels of APN, MCP-1, hs-CRP, and SOD in patients with hypertension and diabetes mellitus (DM) and to investigate the correlations among these inflammatory factors. The study aimed to provide insights into disease monitoring and management. Methods: 320 cases were included in this study, including 50 cases in group A (simple diabetes mellitus); 60 cases in group B (simple hypertension); and 90 cases in group C (Hypertension with diabetes). 120 healthy subjects served as the control group. Fasting blood glucose (FPG), glycosylated hemoglobin (GHbA1c) and other biochemical indicators were detected, and ELISA detected the levels of MCP-1, APN and SOD, hs-CRP was detected by immunoenhanced turbidimetric method. Results: Patients with diabetes (group A), hypertension (group B), and hypertension with diabetes (group C) exhibited elevated FPG, GHbA1c, hs-CRP, and MCP-1 levels and decreased APN and SOD levels compared to the control group (P < .05). In patients with hypertension and diabetes (group C), FPG and GHbA1c levels were positively correlated with MCP-1 and hs-CRP, while APN levels showed a negative correlation with these inflammatory markers(P < .05). SOD levels were positively correlated with MCP-1, APN, and hs-CRP levels in group C patients (P < .05). Conclusion: These results suggest that APN, MCP-1, hs-CRP, and SOD are important factors in the development of atherosclerosis in patients with comorbid hypertension and diabetes. Monitoring these biomarkers may guide disease management strategies.
ABSTRACT
Background and Objectives: Oxidative stress is implicated in the progression of nonalcoholic steatohepatitis (NASH) through the triggering of inflammation. Deuterium-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to the reactive oxygen species (ROS)-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-) PUFAs. Here, we aimed to investigate the impacts of D-PUFAs on oxidative stress and its protective effect on NASH. Materials and Methods: C57BL/6 mice were randomly divided into three groups and were fed a normal chow diet, a methionine-choline-deficient (MCD) diet, and an MCD with 0.6% D-PUFAs for 5 weeks. The phenotypes of NASH in mice were determined. The levels of oxidative stress were examined both in vivo and in vitro. Results: The treatment with D-PUFAs attenuated the ROS production and enhanced the cell viability in tert-butyl hydroperoxide (TBHP)-loaded hepatocytes. Concurrently, D-PUFAs decreased the TBHP-induced oxidative stress in Raw 264.7 macrophages. Accordingly, D-PUFAs increased the cell viability and attenuated the lipopolysaccharide-stimulated proinflammatory cytokine expression of macrophages. In vivo, the administration of D-PUFAs reduced the phenotypes of NASH in MCD-fed mice. Specifically, D-PUFAs decreased the liver transaminase activity and attenuated the steatosis, inflammation, and fibrosis in the livers of NASH mice. Conclusion: D-PUFAs may be potential therapeutic agents to prevent NASH by broadly reducing oxidative stress.
Subject(s)
Choline Deficiency , Non-alcoholic Fatty Liver Disease , Animals , Humans , Mice , Choline Deficiency/complications , Choline Deficiency/metabolism , Deuterium , Diet , Disease Models, Animal , Fatty Acids, Unsaturated/pharmacology , Inflammation/drug therapy , Liver/metabolism , Methionine/pharmacology , Methionine/therapeutic use , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/prevention & control , Oxidative Stress , Reactive Oxygen Species/metabolismABSTRACT
Multiplex assays, involving the simultaneous use of multiple circulating tumor DNA (ctDNA) markers, can improve the performance of liquid biopsies so that they are highly predictive of cancer recurrence. We have developed a single-tube methylation-specific quantitative PCR assay (mqMSP) that uses 10 different methylation markers and is capable of quantitative analysis of plasma samples with as little as 0.05% tumor DNA. In a cohort of 179 plasma samples from colorectal cancer (CRC) patients, adenoma patients, and healthy controls, the sensitivity and specificity of the mqMSP assay were 84.9% and 83.3%, respectively. In a head-to-head comparative study, the mqMSP assay also performed better for detecting early-stage (stage I and II) and premalignant polyps than a published SEPT9 assay. In an independent longitudinal cohort of 182 plasma samples (preoperative, postoperative, and follow-up) from 82 CRC patients, the mqMSP assay detected ctDNA in 73 (89.0%) of the preoperative plasma samples. Postoperative detection of ctDNA (within 2 wk of surgery) identified 11 of the 20 recurrence patients and was associated with poorer recurrence-free survival (hazard ratio, 4.20; P = 0.0005). With subsequent longitudinal monitoring, 14 patients (70%) had detectable ctDNA before recurrence, with a median lead time of 8.0 mo earlier than seen with radiologic imaging. The mqMSP assay is cost-effective and easily implementable for routine clinical monitoring of CRC recurrence, which can lead to better patient management after surgery.
