Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies

Immune cells are essential for initiating and developing the fibrotic process by releasing cytokines and growth factors that activate fibroblasts and promote extracellular matrix deposition. Immunometabolism describes how metabolic alterations affect the function of immune cells and how inflammation and immune responses regulate systemic metabolism. The disturbed immune cell function and their interactions with other cells in the tissue microenvironment lead to the origin and advancement of fibrosis. Understanding the dysregulated metabolic alterations and interactions between fibroblasts and the immune cells is critical for providing new therapeutic targets for fibrosis. This review provides an overview of recent advances in the pathophysiology of fibrosis from the immunometabolism aspect, highlighting the altered metabolic pathways in critical immune cell populations and the impact of inflammation on fibroblast metabolism during the development of fibrosis. We also discuss how this knowledge could be leveraged to develop novel therapeutic strategies for treating fibrotic diseases

High expression of ubiquitin-conjugating enzyme 2C (UBE2C) correlates with nasopharyngeal carcinoma progression

BACKGROUND: Overexpression of ubiquitin-conjugating enzyme 2C (UBE2C) has been detected in many types of human cancers, and is correlated with tumor malignancy. However, the role of UBE2C in human nasopharyngeal carcinoma (NPC) is unclear. In this study, we investigated the role of aberrant UBE2C expression in the progression of human NPC. METHODS: Immunohistochemical analysis was performed to detect UBE2C protein in clinical samples of NPC and benign nasopharyngeal tissues, and the association of UBE2C expression with patient clinicopathological characteristics was analyzed. UBEC2 expression profiles were evaluated in cell lines representing varying differentiated stages of NPC and immortalized nasopharyngeal epithelia NP-69 cells using quantitative RT-PCR, western blotting and fluorescent staining. Furthermore, UBE2C was knocked down using RNA interference in these cell lines and proliferation and cell cycle distribution was investigated. RESULTS: Immunohistochemical analysis revealed that UBE2C protein expression levels were higher in NPC tissues than in benign nasopharyngeal tissues (P<0.001). Moreover, high UBE2C protein expression was positively correlated with tumor size (P=0.017), lymph node metastasis (P=0.016) and distant metastasis (P=0.015) in NPC patients. In vitro experiments demonstrated that UBE2C expression levels were inversely correlated with the degree of differentiation of NPC cell lines, whereas UBE2C displayed low level of expression in NP-69 cells. Knockdown of UBE2C led to significant arrest at the S and G2/M phases of the cell cycle, and decreased cell proliferation was observed in poorly-differentiated CNE2Z NPC cells and undifferentiated C666-1 cells, but not in well-differentiated CNE1 and immortalized NP-69 cells. CONCLUSIONS: Our findings suggest that high expression of UBE2C in human NPC is closely related to tumor malignancy, and may be a potential marker for NPC progression

Inhibition of Notch Signaling Attenuates Schistosomiasis Hepatic Fibrosis via Blocking Macrophage M2 Polarization.

Macrophages play a key role in the pathogenesis of liver granuloma and fibrosis in schistosomiasis. However, the underlying mechanisms have not been fully characterized. This study revealed that the macrophages infiltrating the liver tissues in a murine model of Schistosoma japonica infection exhibited M2 functional polarization, and Notch1/Jagged1 signaling was significantly upregulated in the M2 polarized macrophages in vivo and in vitro. Furthermore, the blockade of Notch signaling pathway by a γ-secretase inhibitor could reverse macrophage M2 polarization in vitro and alleviate liver granuloma and fibrosis in the murine model of schistosomiasis. These results implied that the Notch1/Jagged1 signaling-dependent M2 polarization of macrophages might play an important role in liver granuloma and fibrosis in schistosomiasis, and the inhibition of Notch1/Jagged1 signaling might provide a novel therapeutic approach to administrate patients with schistosomiasis

Inverse Estimation of Effective Moisture Diffusivity in Lumber during Drying Using Genetic Algorithms

This article presents a methodology based on genetic algorithms (GA) optimization with a three-dimensional numerical solution to the diffusion model obtained by using the finite volume method (FVM) for determining the effective moisture diffusivity in lumber. The objective or error function between measured and simulated drying curves was obtained, and the effective moisture diffusivity parameters with greatest correspondence between measured and estimated values were obtained. As a result, a new equation for effective moisture diffusivity was proposed, which depends on lumber moisture content and drying temperature. Effective moisture diffusivities ranged from 1.120 × 10-9 to 1.277 × 10-8 m2/s. Finally, the proposed coefficients were validated by experiments. The drying kinetics were successfully simulated with the optimized effective moisture diffusivity model

Evaluation Model Construction and Simulation Research on Tourist Diversion Strategy in Ecotourism Scenery Sport

Abstract: Due to unbalanced distribution of tourists during peak time, tourists are likely to highly flock in certain areas of scenery spots if imperfect organization and management. For this reason, there may be crowds or even trample accidents in addition to unrecoverable damages for the ecological environment in such areas. Therefore, the valid solution is to formulate scientific tourist diversion strategy, reasonably adjust the tour routes, and realize the balanced distribution of tourists over space and time. The prerequisite and base of the research is to establish scientific rational evaluation indicators for diversion strategy. At present, the common indicators include the Variance Model reflecting the balance of load rate for each spot in the scenic region and the Gini-Simpson Index (G-S Index) showing the dispersion degrees of tourists among the scenery spots. However, these indexes highlight the opinions of scenery region managers but ignore the tourism utility during the travel. Such indexes can be used to evaluate the diversion strategy only from a macro view but hardly facilitates shaping any scientific valid suggestions for plan improvement. So this thesis established the evaluation model of tourism utility function (TUF) based on the spot congestion degree and compared the simulation effects of three diversion strategies respectively with three evaluation models, including Variance, G-S Index and TUF. It is found from the comparison results that TUF can better the overall evaluation of the diversion strategies and reveal the relevant inherent problems so as to provide reasonable and suggestions for scientific management on the scenery spot

Inhibition of Notch signaling by a γ-secretase inhibitor attenuates hepatic fibrosis in rats.

Notch signaling is essential to the regulation of cell differentiation, and aberrant activation of this pathway is implicated in human fibrotic diseases, such as pulmonary, renal, and peritoneal fibrosis. However, the role of Notch signaling in hepatic fibrosis has not been fully investigated. In the present study, we show Notch signaling to be highly activated in a rat model of liver fibrosis induced by carbon tetrachloride (CCl(4)), as indicated by increased expression of Jagged1, Notch3, and Hes1. Blocking Notch signaling activation by a γ-secretase inhibitor, DAPT, significantly attenuated liver fibrosis and decreased the expression of snail, vimentin, and TGF-β1 in association with the enhanced expression of E-cadherin. The study in vitro revealed that DAPT treatment could suppress the EMT process of rat hepatic stellate cell line (HSC-T6). Interestingly, DAPT treatment was found not to affect hepatocyte proliferation in vivo. In contrast, DAPT can inhibit hepatocyte apoptosis to some degree. Our study provides the first evidence that Notch signaling is implicated in hepatic fibrogenesis and DAPT treatment has a protective effect on hepatocytes and ameliorates liver fibrosis. These findings suggest that the inhibition of Notch signaling might present a novel therapeutic approach for hepatic fibrosis

DAPT attenuates hepatic granulomata and fibrosis in murine schistosomiasis.

<p>(A) The pathological changes and collagen deposition were assessed by Hematoxylin and eosin and Masson’s trichrome staining. (B) The result of semi-quantitative analysis of the Masson’s trichrome staining. (C) Assay of hydroxyproline content. (D) Mean hepatic granuloma diameter (mm). Data from the three independent experiments represent the results of eight mice in each group. *: <i>P</i> < 0.05 versus mice in the model group.</p

SEA upregulates Notch1/Jagged1 signaling in M2 macrophages in vitro.

<p>(A) RAW264.7 cells were treated with SEA (40 μg/ml) or PBS for two hours. The mRNA expression of Notch receptors, Jagged1 and Jagged2 in the RAW264.7 cells were assessed by real-time PCR. (B and C) The mRNA levels of Notch1, Jagged1 and Hes1 in RAW264.7 cells stimulated with SEA (40 μg/ml) for the indicated time or with increasing concentration of SEA for two hours was assayed by real-time PCR. (D and E) The protein expression of Notch1, Jagged1 and Hes1 in RAW264.7 cells treated with SEA (40 μg/ml) for the indicated time was determined by Western blot analysis. Data shown are representative the three independent experiments. In compared with the control group, *: <i>p</i> < 0.05, **: <i>p</i> < 0.01.</p

The infiltrated macrophages in liver tissues exhibit M2 polarization in schistosomiasis mice.

<p>After eight weeks of cercariae or PBS administration liver sections of mice were stained with antibodies against F4/80⁺, Arg-1 and CD206. Nuclei were stained with DAPI. Images were taken by confocal fluorescent microscopy. Arrows indicate F4/80⁺/Arg-1 or F4/80⁺/CD206 double positive cells, and the bars represent 20 μm.</p

DAPT blocks SEA-induced macrophage M2 polarization by inhibiting Notch signaling.

<p>RAW264.7 cells were administrated with DAPT (0.4 μmol/l) or DMSO (0.1%) for twelve hours, and then stimulated with SEA (40 μg/ml) or PBS for two hours. (A) The expression of Notch1, Jagged1 and Hes1 in the RAW264.7 cells was determined by Western blot. (B) The levels of IL-10 and IL-12 in the supernatants were assessed by ELISA. (C) The expression of Arg-1 and NOS-2 in the RAW264.7 cells was assessed by Western blot. All data represent the results of three independent experiments. In compared with the control group, *: <i>p</i> < 0.05. 1 indicates DAPT+SEA; 2 indicates DMSO+SEA.</p