- TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression. [Journal Article]
- MIMol Immunol 2018 May 21; 99:171-181
- Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initia...
Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl4) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4+CD25+ Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl4/CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.
- Segmentation of histological images and fibrosis identification with a convolutional neural network. [Journal Article]
- CBComput Biol Med 2018 May 16; 98:147-158
- Segmentation of histological images is one of the most crucial tasks for many biomedical analyses involving quantification of certain tissue types, such as fibrosis via Masson's trichrome staining. H...
Segmentation of histological images is one of the most crucial tasks for many biomedical analyses involving quantification of certain tissue types, such as fibrosis via Masson's trichrome staining. However, challenges are posed by the high variability and complexity of structural features in such images, in addition to imaging artifacts. Further, the conventional approach of manual thresholding is labor-intensive, and highly sensitive to inter- and intra-image intensity variations. An accurate and robust automated segmentation method is of high interest. We propose and evaluate an elegant convolutional neural network (CNN) designed for segmentation of histological images, particularly those with Masson's trichrome stain. The network comprises 11 successive convolutional - rectified linear unit - batch normalization layers. It outperformed state-of-the-art CNNs on a dataset of cardiac histological images (labeling fibrosis, myocytes, and background) with a Dice similarity coefficient of 0.947. With 100 times fewer (only 300,000) trainable parameters than the state-of-the-art, our CNN is less susceptible to overfitting, and is efficient. Additionally, it retains image resolution from input to output, captures fine-grained details, and can be trained end-to-end smoothly. To the best of our knowledge, this is the first deep CNN tailored to the problem of concern, and may potentially be extended to solve similar segmentation tasks to facilitate investigations into pathology and clinical treatment.
- Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients with Child-Pugh Class B and C Cirrhosis: A Multicenter Study. [Journal Article]
- IJInt J Infect Dis 2018 May 21
- CONCLUSIONS: These results suggested that the recommended and halved maintenance dose may inappropriate for the higher Cmin in patients with Child-Pugh class B and C cirrhosis and voriconazole Cmin should be monitored earlier to avoid AEs.
- Fetal supraventricular tachycardia and cystic fibrosis: coincidence or association? Two case reports. [Journal Article]
- JGJ Gynecol Obstet Hum Reprod 2018 May 21
- PCL/EUG scaffolds with tunable stiffness can regulate macrophage secretion behavior. [Review]
- PBProg Biophys Mol Biol 2018 May 21
- Osteoarthritis (OA) is a prevalent joint disorder worldwide. Recent studies suggested that macrophages play an important role in the progression of OA. However, the detailed pathology related to macr...
Osteoarthritis (OA) is a prevalent joint disorder worldwide. Recent studies suggested that macrophages play an important role in the progression of OA. However, the detailed pathology related to macrophages is still ambiguous, especially those related to mechanotransduction. In this study, PCL/EUG composite scaffolds were first fabricated by electrospinning. The stiffness of as-fabricated scaffolds was controlled by adjusting the PCL-versus-EUG ratio. The mechanical properties, structural characterics and chemical composition of the scaffolds were investigated using various materials characterization techniques. The results showed that the stiffness of the scaffolds was in the same range as the cartilage tissues with OA. Confocal microscope and RT-PCR were performed to investigate the macrophages cultured on the scaffolds. Significant morphological change of cells was observed. The expression of inflammatory and fibrosis-related cytokines increases as the scaffold stiffness decreases, similar to the trend observed in OA progression.
- Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence. [Journal Article]
- JCJ Control Release 2018 May 21
- So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (VA) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mec...
So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (VA) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to VA and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled VA-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, VA-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.
- Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. [Journal Article]
- JMJ Mol Cell Cardiol 2018 May 21
- CONCLUSIONS: DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.
- Portal Vein Thrombosis: Imaging the Spectrum of Disease With an Emphasis on MRI Features. [Journal Article]
- AAAJR Am J Roentgenol 2018 May 24; :1-11
- CONCLUSIONS: PVT may be a complication of liver cirrhosis, but it may also occur as a primary vascular disorder without liver disease. PVT can result in portal hypertension and may present with variceal bleeding or hypersplenism. Radiologists should be familiar with the imaging of PVT in patients of various ages and in different clinical scenarios. PVT can influence hepatic perfusion, the shape of the bile ducts, and liver architecture. Bland PVT and tumor-related PVT have major implications for hepatic transplant.
- Neonatal intake of oleanolic acid attenuates the subsequent development of high fructose diet-induced non-alcoholic fatty liver disease in rats. [Journal Article]
- JDJ Dev Orig Health Dis 2018 May 24; :1-11
- Dietary manipulations during the early postnatal period are associated with the development of metabolic disorders including non-alcoholic fatty liver disease (NAFLD) or long-term protection against ...
Dietary manipulations during the early postnatal period are associated with the development of metabolic disorders including non-alcoholic fatty liver disease (NAFLD) or long-term protection against metabolic dysfunction. We investigated the potential hepatoprotective effects of neonatal administration of oleanolic acid (OA), a phytochemical, on the subsequent development in adulthood, of dietary fructose-induced NAFLD. Male and female suckling rats (n=112) were gavaged with; distilled water (DW), OA (60 mg/kg), high fructose solution (HF; 20% w/v) and OA+HF (OAHF) for 7 days. The rats were weaned onto normal rat chow on day 21 up to day 55. From day 56, half of the rats in each treatment group were continued on plain water or HF as drinking fluid for 8 weeks. Hepatic lipid accumulation and hepatic histomorphometry were then determined. Fructose consumption in adulthood following neonatal fructose intake (HF+F) caused a 47-49% increase in hepatic lipid content of both male and female rats (P<0.05). However, fructose administered in adulthood only, caused a significant increase (P<0.05) in liver lipid content in females only. NAFLD activity scores for inflammation and steatosis were higher in the fructose-fed rats compared with other groups (P<0.05). Steatosis, low-grade inflammation and fibrosis were observed in rats that received HF+F. NAFLD area fraction for fibrosis was three times higher in rats that received fructose neonatally and in adulthood compared with the rats in the negative control group (P<0.05). Treatment with OA during a critical window of developmental plasticity in rats prevented the development of fructose-induced NAFLD.
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- Cell Division Cycle 7-Kinase is a negative regulator of cell-mediated collagen degradation. [Journal Article]
- AJAm J Physiol Lung Cell Mol Physiol 2018 May 24
- Although extensive work has delineated many of the mechanisms of extracellular matrix (ECM) production, far less is known about pathways that regulate ECM degradation. This is particularly true of ce...
Although extensive work has delineated many of the mechanisms of extracellular matrix (ECM) production, far less is known about pathways that regulate ECM degradation. This is particularly true of cellular internalization and degradation of matrix, which play an underappreciated role in ECM metabolism and lung fibrosis. For example, genetic perturbation of this pathway leads to exacerbated fibrosis in experimental animal models. In this work, we present the results of an unbiased screen of Drosophila phagocytes that yielded multiple genes that when silenced led to increased collagen uptake. We further describe the function of Cell Division Cycle 7-Kinase (CDC7) as a specific suppressor of collagen uptake. We show that the genetic or pharmacologic inhibition of CDC7 results in increased expression of the collagen endocytic receptor Endo180. Chromobox 5 (CBX5) is a putative target of CDC7 and genetic silencing of CBX5 also results in increased Endo180 and collagen uptake. Finally, CRISPR-mediated activation of Endo180 expression results in increased collagen uptake, suggesting that CDC7 regulates collagen internalization through increased Endo180 expression. Targeting the regulatory elements of the collagen degradative machinery may be a useful therapeutic approach in diseases of fibrosis or malignancy.