Although midnolin has been studied for over 20 years, its biological roles in vivo remain largely unknown, especially due to the lack of a functional animal model. Indeed, given our recent discovery ...that the knockdown of midnolin suppresses liver cancer cell tumorigenicity and that this antitumorigenic effect is associated with modulation of lipid metabolism, we hypothesized that knockout of midnolin in vivo could potentially protect from nonalcoholic fatty liver disease (NAFLD) which has become the most common cause of chronic liver disease in the Western world. Accordingly, in the present study, we have developed and now report on the first functional global midnolin knockout mouse model. Although the overwhelming majority of global homozygous midnolin knockout mice demonstrated embryonic lethality, heterozygous knockout mice were observed to be similar to wild-type mice in their viability and were used to determine the effect of reduced midnolin expression on NAFLD. We found that global heterozygous midnolin knockout attenuated the severity of NAFLD in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism. Collectively, our results support a role for midnolin in regulating cholesterol/lipid metabolism in the liver. Thus, midnolin may represent a novel therapeutic target for NAFLD. Finally, our observation that midnolin was essential for survival underscores the broad importance of this gene beyond its role in liver biology.
We have developed and now report on the first functional global midnolin knockout mouse model. We found that global heterozygous midnolin knockout attenuated the severity of nonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose, and this attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.
The hexavalent chromium (Cr(VI)) removal capacity of acid-washed zerovalent iron (AW-Fe0) was evaluated under different groundwater geochemistry conditions through column experiments. It was found ...that each gram of the AW-Fe0 could remove 0.65-1.76 mg of Cr(VI) from synthetic groundwater in the absence of bicarbonate (HCO3-), magnesium and/or calcium ions. Groundwater geochemistry was found to exert various degrees of impact on Cr(VI) removal by the AW-Fe0, in which HCO3- alone gave the mildest impact whereas the copresence of calcium and HCO3- exerted the greatest impact In comparison with the unwashed Fe0, the AW-Fe0 showed a poorer Cr(VI) removal capacity and was also more susceptible to the influence of the dissolved groundwater constituents on Cr(VI) removal,thereby indicating the unsuitability of using AW-Fe0 in permeable reactive barriers for remediation of Cr(VI)-contaminated groundwater. On the AW-Fe0 surface, where the indigenous iron precipitates were almost erased, trivalent chromium including chromium (III) oxides, hydroxides, and oxyhydroxides in irregular strip, chick footmark-liked or boulder-liked forms as well as Cr(III)-Cr(VI) mixed oxides were detected.
Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier ...pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution.
The effects of humic acid (HA) on As(V) removal by zero-valent iron (Fe
0) from groundwater, associated with corrosion products analyses, were investigated using batch experiments. It was found that ...arsenic was rapidly removed from groundwater possibly due to its adsorption and co-precipitation with the corrosion products of Fe
0. The removal rate of arsenic by Fe
0 was inhibited in the presence of HA probably because of the formation of soluble Fe-humate in groundwater which hindered the production of iron precipitates. A longer reaction time was then required for arsenic removal. Such an influence of HA on arsenic removal increased with increasing HA concentration from 5 to 25
mg
L
−1. The binding capacity of HA for dissolved Fe was estimated to be about 0.75
mg Fe
mg
−1 HA. When the complexation of HA with dissolved Fe was saturated, further corrosion of Fe
0 would produce precipitates, which significantly accelerated the removal of arsenic from groundwater via adsorption and co-precipitation with the corrosion products. Iron (hydr)oxides such as maghemite, lepidocrocite, and magnetite were characterized by XRD analyses as the corrosion products, while As(V) was found on the surface of these corrosion products as detected by fourier transform infrared spectrometry and X-ray photoelectron spectroscopy.
Cholangiocarcinoma is the second most common primary liver malignant neoplasm. It usually affects older individuals in their seventh decade of life with no gender predilection. Recently, a distinct ...subtype of cholangiocarcinoma has emerged with 2 proposed names: “cholangioblastic” and “solid tubulocystic.” This variant predominantly occurs in younger women who lack the common risk factors for patients diagnosed with cholangiocarcinomas, such as older age and chronic liver disease or cirrhosis. We describe 3 new patients with a cholangioblastic variant of intrahepatic cholangiocarcinoma. At the time of diagnosis, the patients were aged 19-, 46-, and 28-year-old; 2 females and 1 male (the 46-year-old). None of our patients had a history of chronic liver disease or known predisposing factors for liver tumors. Tumor size ranged from 2.3 to 23 cm in greatest dimension. Histological examination of these tumors demonstrated reproducible morphology characterized by trabecular, nested, and multicystic patterns with micro and macro follicles filled with eosinophilic material. The immunohistochemical profile showed that the tumor cells were positive for keratin 7, inhibin, synaptophysin, and albumin in situ hybridization, while negative for HepPar1, arginase, and INSM1. All tumors lacked conventional intrahepatic cholangiocarcinoma/adenocarcinoma morphology. We also review the literature and emphasize that neuroendocrine tumors should be recognized as a major diagnostic pitfall of this variant.
The World Health Organization estimates that there is greater than one million new cases of sexually transmitted infections (STIs) every day. In many countries, STIs are at an unprecedented high, ...including the USA, where nearly 20 million new cases were reported in 2016. Although morbidity associated with STIs is usually seen in the context of genitourinary disease, these pathogens may also affect the gastrointestinal tract and cause anal pain, abdominal pain, or diarrhea. It is important to recognize patterns of injury associated with these pathogens, especially those that may mimic other gastrointestinal diseases, such as idiopathic inflammatory bowel disease (IBD). This review focuses upon STIs of the lower gastrointestinal tract, organized by the most common site of involvement: the anus, rectum, and colon.
Objectives: A subset of colon cancers originates from sessile serrated adenomas/polyps (SSA/Ps). Our goal was to identify markers for SSA/Ps that could aid in distinguishing them from hyperplastic ...polyps (HPs).
Methods: We performed immunostaining for gastric proteins MUC5AC and TFF1 in formalin-fixed, paraffin-embedded (FFPE) samples of HPs (n = 47), SSA/Ps (n = 37), and normal colon (n = 30).
Results: Control mucosa expressed only trace amounts of MUC5AC and TFF1. HPs exhibited an 11.3- and 11.4-fold increase in MUC5AC and TFF1 expression confined to the upper segments of the crypts near the luminal surface of the polyps. SSA/Ps displayed on average 1.6-fold (MUC5AC, P < .008) and 1.4-fold (TFF1, P < .03) higher signal intensity for these markers than HPs, with a dramatic coexpression of MUC5AC and TFF1 typically occupying the entire length of the crypt. Immunoperoxidase results were similar to immunofluorescence staining for both MUC5AC and TFF1.
Conclusions: Our results suggest that the analysis of expression of MUC5AC and TFF1 may be useful for differentiating SSA/Ps from HPs. We also suggest the possibility that crypt morphology may be at least partly due to overproduction of highly viscous gastric mucins and that these proteins may play a role in the serrated pathway to colon carcinogenesis.
Zero-valent iron (Fe
0) was used to remove hexavalent chromium, Cr(VI), in groundwater via a coupled reduction-oxidation reaction. Nine columns were set up under various groundwater geochemistry to ...investigate the effects of hardness and carbonate on Cr(VI) removal. The Cr(VI) removal capacity of Fe
0 was found to be about 4
mg
Cr/g Fe
0 in the control column (i.e., column 1). A slight decrease in the Cr(VI) removal capacity was found in the presence of calcium hardness. However, there was a 17% drop in the Cr(VI) removal capacity when magnesium hardness was present at low to moderately hard level. Results also revealed that carbonate changed the morphology of the Fe
0 by formation of pale green precipitates on the iron filings. Furthermore, there was a 33% decrease in the Cr(VI) removal capacity of Fe
0 when both carbonate and hardness ions were present. In general, the presence of hardness ions and carbonate in groundwater have great impact on the Fe
0 by formation of passivated precipitates, such as CaCO
3, on the Fe
0 surface resulting in a diminished lifespan of the Fe
0 by blocking electron transfer.
Collagen production by activated hepatic stellate cells (HSCs) to encapsulate injury is part of the natural wound-healing response in injured liver. However, persistent activation of HSCs can lead to ...pathological fibrogenesis. Such persistent HSC activation could be mediated by norepinephrine (NE), a reaction product of dopamine beta-hydroxylase (DBH).
To investigate the potential paracrine role of NE in hepatotoxin thioacetamide (TAA)-induced liver fibrosis.
In TAA-treated mice, fibrotic liver tissue showed significant increases in the mRNA expression of DBH up to 14-fold and collagen up to 7-fold. Immunohistochemical staining showed increased DBH protein expression in fibrotic liver tissue. Parenchymal hepatocyte cell line HepG2 expressed DBH and secreted NE, and the conditioned medium of HepG2 cells promoted collagenesis in nonparenchymal HSC cell line LX-2. TAA treatment increased DBH expression by 170% in HepG2 cells, as well as increased NE by 120% in the conditioned medium of HepG2 cells. The conditioned medium of TAA-treated HepG2 cells was used to culture LX-2 cells, and was found to increase collagen expression by 80% in LX-2 cells. Collagen expression was reduced by pre-treating HepG2 cells with siRNA targeting DBH or by adding NE antagonists to the conditioned medium.
Finally, TAA-induced oxidative stress in HepG2 cells was associated with induction of DBH expression. Collectively, our results suggest a potential role for DBH/NE-mediated crosstalk between hepatocytes and HSCs in fibrogenesis.
From a therapeutic standpoint, antagonism of DBH/NE induction in hepatocytes might be a useful strategy to suppress pathological fibrogenesis.
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