Lijing Wang

Atherosclerosis is the most common disease of the vascular system and the metabolic disorder is one of its important molecular mechanisms. SAP protein is found to be highly expressed in atherosclerotic blood vessels. Our previous study found that SAP deficiency can significantly inhibit the development of atherosclerosis. However, the regulatory effect of SAP deficiency on AS metabolism is unknown. Based on ¹H-NMR metabonomics, this study investigated the serum metabolic changes in ApoE^−/−;SAP^−/− mice compared with ApoE^−/− mice during the whole progression of atherosclerosis. The results showed that acetate, pyruvate, choline and VLDL + LDL were statistically regulated to the normal levels as in C57 mice by SAP deficiency in ApoE^−/−;SAP^−/− mice at 8 w (without obvious plaques). With the appearance and aggravation of atherosclerotic plaques (8 + 4 w and 8 + 8 w), the four metabolites of acetate, pyruvate, choline and VLDL + LDL were continuously regulated, which were denoted as the metabolic regulatory markers of SAP deficiency. We also found that the changes in these four metabolites had nothing to do with high-fat diet. Therefore, it was revealed that SAP deficiency regulated the metabolic disorders in ApoE^−/− prior to the appearance of obvious atherosclerotic plaques, which is one of the important mechanisms leading to the inhibition of atherosclerosis, providing a new basis for the application of SAP in atherosclerosis.

Atrial natriuretic peptide (ANP) activity deficiency contributes to salt-sensitive hypertension in humans and mice. However, the role of ileal microbiota in salt sensitivity in ANP deficiency-related cardiac injury has not been investigated yet. This study used ANP^−/− mice to analyze the role of the salt-sensitive ileal microbiome on cardiac injury. ANP^−/− mice showed an increase in blood pressure (BP), the heart weight/body weight (HW/BW) ratio, and cardiac hypertrophy compared with wild-type (WT) mice. ANP deficiency did not impact the histological structure but reduced occludin expression in the ileum. Antibiotics significantly relieved BP and cardiac hypertrophy in ANP^−/− mice. A high-salt diet (HSD) increased BP, the HW/BW ratio, and cardiac hypertrophy/fibrosis in WT and ANP^−/− mice, and an HSD treatment in ANP^−/− mice exacerbated these cardiac parameters. The HSD markedly decreased muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of WT and ANP^−/− mice. Furthermore, the HSD increased the level of TLR4 and IL-1β in ANP^−/− mice ileum compared with WT mice. Antibiotics reduced the HW/BW ratio, cardiac hypertrophy/fibrosis, and the level of TLR4 and IL-1β in the ileum, and rescued the muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of HSD-ANP^−/− mice. Importantly, ANP deficiency induced the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum on the NSD diet, which was only observed in HSD-induced WT mice but not in WT mice on the NSD. Besides, the HSD significantly enhanced the sum of the percentage of the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum of ANP^−/− mice. Ileal microbiota transfer (IMT) from ANP^−/− mice to healthy C57BL/6J mice drove Lactobacillus johnsonii and Lactobacillus reuteri colonization in the ileum, which manifested an increase in BP, the HW/BW ratio, cardiac hypertrophy, and ileal pathology compared with IMT from WT mice. The HSD in C57BL/6J mice with IMT from ANP^−/− mice drove the colonization of Burkholderiales bacterium YL45, Lactobacillus johnsonii, and Lactobacillus reuteri in the ileum and further exacerbated the cardiac and ileal pathology. Our results suggest that salt-sensitive ileal microbiota is probably related to ANP deficiency-induced cardiac injury.

Background: Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. Apc^Min/+mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the Apc^Min/+mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when Apc^Min/+mice were crossed with MMP12^−/−mice, indicating that MMP12 has a role in age-related Apc^Min/+-associated weight loss. As a control, the weight of MMP12^−/−mice on a weekly basis, their weight were not significantly different from those of WT mice.Methods: Apc^Min/+; MMP12^−/−mice were obtained by crossing Apc^Min/+mice with MMP12 knockout (MMP12^−/−) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of Apc^Min/+mice.Results: MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in Apc^Min/+mice, while inhibiting MMP12 could suppress weight loss in Apc^Min/+mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of Apc^Min/+mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage.Conclusions: MMP12 is essential for controlling body weight of Apc^Min/+mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

Aim: Although studies on lncRNAs in renal fibrosis have focused on target genes and functions of lncRNAs, a comprehensive interaction analysis of lncRNAs is lacking. Materials & methods: Differenti...

Background: Slit2 is a member of the Slit family of secreted glycoproteins that plays highly conserved roles in neuronal axon guidance and cellular migration. Our previous experimental results showed Alzheimer's disease-like alterations and increased permeability of the blood–brain barrier in Slit2-overexpressing transgenic (Slit2-Tg) mice aged 8–9 months. Nevertheless, relatively little is known about behavioral alterations in adult Slit2-Tg mice (2–6 months of age). To observe the age-related behavioral effects of Slit2 overexpression in adult mice, we performed a battery of behavioral tests with adult Slit2-Tg mice at 2–6 months of age.Results: The body weight of Slit2-Tg mice was lower than that of the wild-type mice from 15 weeks of age. Compared with the control mice, depression-like behaviors were found in Slit2-Tg mice from 15 to 21 weeks of age in the sucrose preference test, although Slit2-Tg mice were hyperactive in the tail suspension test. The anxiety-like behaviors were found in Slit2-Tg mice in the open field test, as well as increased locomotor activity. The anxiety-like behaviors were also found in adult Slit2-Tg mice in the elevated plus maze. Compared to wild-type mice at 23 weeks old, impairment of the hippocampal neurons were found in Slit2-Tg mice at the same age in hematoxylin–eosin staining (H&E), including some eccentric dispersion and expansion of neuronal bodies. In addition, the messenger RNA (mRNA) expression of TNF-α was elevated in the hippocampus of adult Slit2-Tg mice.Conclusions: Slit2 overexpression causes depression-/anxiety-like behaviors in adult mice that may be related to an increase in inflammatory factors and damage to hippocampal neurons.

Weight loss and muscle wasting can have devastating impacts on survival and quality of life of patients with cancer cachexia. Here, we have established a hybrid mouse of Apc ^Min/+ mice and MMP12 knockout mice (Apc ^Min/+ ; MMP12 ^-/- ) and found that knockout MMP12 can suppress the weight and muscle loss of Apc ^Min/+ mice. In detail, we found that interleukin 6 was highly upregulated in the serum of cancer patients and MMP12 was increased in muscle of tumor-bearing mice. Interestingly, the interleukin 6 secreted by tumor cells led to MMP12 overexpression in the macrophages, which further resulted in degradation of insulin and insulin-like growth factor 1 and interruption of glycolipid metabolism. Notably, depletion of MMP12 prevented weight loss of Apc ^Min/+ mice. Our study uncovers the critical role of MMP12 in controlling weight and highlights the great potential of MMP12 in the treatment of cancer cachexia.

The author wishes to make the following correction to this paper

Background: Leading to a sustained epidemic spread with >2,000,000 confirmed human infections, including >100,000 deaths, COVID-19 was caused by SARS-CoV-2 and resulted in acute respiratory distress syndrome (ARDS) and sepsis, which brought more challenges to the patient’s treatment. The S-glycoprotein, which recognized as the key factor for the entry of SARS-CoV-2 into the cell, contains two functional domains: an ACE2 receptor binding domain and a second domain necessary for fusion of the coronavirus and cell membranes. FURIN activity, exposes the binding and fusion domains, is essential for the zoonotic transmission of SARS-CoV-2. Moreover, it has been reported that ACE2 is likely to be the receptor for SARS-CoV-2. In addition, FURIN enzyme and ACE2 receptor were expressed in airway epithelia, cardiac tissue, and enteric canals, which considered as the potential target organ of the virus. However, report about the expression of FURIN and ACE2 in oral tissues was limited. Methods: In order to investigate the potential infective channel of new coronavirus in oral cavity, we analyze the expression of ACE2 and FURIN that mediate the new coronavirus entry into host cells in oral mucosa using the public single-cell sequence datasets. Furthermore, immunohistochemical staining experiment was performed to confirm the expression of ACE2 and FURIN in the protein level. Results: The bioinformatics results indicated the differential expression of ACE2 and FURIN on epithelial cells of different oral mucosal tissues and the proportion of FURIN-positive cells was obviously higher than that of ACE2-positive cells. IHC experiments revealed that both the ACE2-positive and FURIN-positive cells in the target tissues were mainly positioned in the epithelial layers, partly expressed in fibroblasts, which further confirm the bioinformatics results. Conclusions: Based on these findings, we speculated that SARS-CoV-2 could effectively invade oral mucosal cells though two possible routes: binding to the ACE2 receptor and fusion with cell membrane activated by FURIN protease. Our results indicated that oral mucosa tissues are susceptible to SARS-CoV-2, which provides valuable information for virus-prevention strategy in clinical care as well as daily life.

MMP12 is mainly secreted by macrophages, is involved in macrophage development, and decomposes the extracellular matrix. Herein, we investigated whether macrophages would change in the intestinal tumor microenvironment after MMP12 knockout. Apc^Min/+;MMP12^−/−mice were obtained by crossbreeding Apc^Min/+ mice with MMP12 knockout mice (MMP12^−/− mice). The data showed that the number and volume of intestinal tumors were significantly increased in Apc^Min/+;MMP12^−/− mice compared with Apc^Min/+ mice. Additionally, the tumor biomarkers CA19-9, CEA, and β-catenin appeared relatively early in intestinal tumors in Apc^Min/+;MMP12^−/− mice. The results demonstrated that knocking out MMP12 accelerated the tumor growth and pathological process. On further investigation of its mechanism, the proportions of M2 macrophages in the spleen and among peritoneal macrophages were significantly up-regulated in Apc^Min/+;MMP12^−/− mice. Expression of M2 macrophage-related genes was up-regulated in tumor and peritoneal macrophages. The M2-related cytokine levels of IL-4 and IL-13 were increased in the serum of Apc^Min/+;MMP12^−/−mice. In vitro, bone marrow-derived M2 macrophages were obtained by treating bone marrow cells with IL-4 and IL-13, and these M2 macrophages secreted cytokines being changed. This finding reveals the crucial role of MMP12 in macrophage development and provides a new target for the control of macrophage polarization. Knocking out MMP12 causes intestinal M2 macrophage accumulation in tumor microenvironment, promoting the growth of intestinal tumors in Apc^Min/+ mice.