A novel hypothesis for an alkaline phosphatase ‘rescue’ mechanism in the hepatic acute phase immune response

AbstractThe liver isoform of the enzyme alkaline phosphatase (AP) has been used classically as a serum biomarker for hepatic disease states such as hepatitis, steatosis, cirrhosis, drug-induced liver injury, and hepatocellular carcinoma. Recent studies have demonstrated a more general anti-inflammatory role for AP, as it is capable of dephosphorylating potentially deleterious molecules such as nucleotide phosphates, the pathogenic endotoxin lipopolysaccharide (LPS), and the contact clotting pathway activator polyphosphate (polyP), thereby reducing inflammation and coagulopathy systemically. Yet the mechanism underlying the observed increase in liver AP levels in circulation during inflammatory insults is largely unknown. This paper hypothesizes an immunological role for AP in the liver and the potential of this system for damping generalized inflammation along with a wide range of ancillary pathologies. Based on the provided framework, a mechanism is proposed in which AP undergoes transcytosis in hepatocytes from the canalicular membrane to the sinusoidal membrane during inflammation and the enzyme's expression is upregulated as a result. Through a tightly controlled, nucleotide-stimulated negative feedback process, AP is transported in this model as an immune complex with immunoglobulin G by the asialoglycoprotein receptor through the cell and secreted into the serum, likely using the receptor's State 1 pathway. The subsequent dephosphorylation of inflammatory stimuli by AP and uptake of the circulating immune complex by endothelial cells and macrophages may lead to decreased inflammation and coagulopathy while providing an early upstream signal for the induction of a number of anti-inflammatory gene products, including AP itself

Effects of BPA in Snails

It is an ethical requirement that new findings be presented in light of and in conjunction with a balanced evaluation of the current knowledge and published literature. We believe that Oehlmann et al. (2006) violated this general principle in several ways. For example, the authors inferred that prosobranch snails have a functional estrogen receptor and therefore a much higher sensitivity to estrogens and endocrine-disrupting compounds (EDCs) than other species previously reported in the literature. We found several other problems in their article..

The Carnitine Palmitoyl-Transferase 2 Cascade Hypothesis for Alzheimer’s Disease

Despite decades of intense research, the precise etiology of Alzheimer’s disease (AD) remains unclear. In this hypothesis, we present a new perspective on this matter by identifying carnitine palmitoyl transferase-2 (CPT2) as a central target in AD. CPT2 is an enzyme situated within the inner mitochondrial membrane, playing a crucial role in beta-oxidation of fatty acids. It exhibits high sensitivity to hydrogen peroxide. This sensitivity holds relevance for the etiology of AD, as all major risk factors for the disease share a commonality in producing an excess of hydrogen peroxide right at this very mitochondrial membrane. We will explain the high sensitivity of CPT2 to hydrogen peroxide and elucidate how the resulting inhibition of CPT2 can lead to the characteristic phenotype of AD, thus clarifying its central role in the disease’s etiology. This insight holds promise for the development of therapies for AD which can be implemented immediately

2-chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: a novel mechanism for estrogenicity?

There is increasing concern that certain chemicals in the environment can cause endocrine disruption in exposed humans and wildlife. Investigations of potential effects on endocrine function have been limited mainly to interactions with hormone receptors. A need exists for the development of alternate in vitro methods to evaluate chemicals for their potential to disturb various endocrine functions via other mechanisms. Our laboratory is using the human H295R adrenocortical carcinoma cell line to examine chemicals for their potential to interfere with the activity and/or expression of several key cytochrome P450 (CYP) enzymes involved in the biosynthesis of steroid hormones. In this report we demonstrated that the commonly used 2-chloro-s-triazine herbicides atrazine, simazine, and propazine dose-dependently (0 -30 M) induced aromatase (CYP19) activity to an apparent maximum of about 2.5-fold in H295R cells. Basal-and triazine-induced aromatase activity was completely inhibited by the irreversible aromatase inhibitor 4-hydroxyandrostenedione (100 M). The triazines increased levels of CYP19 messenger ribonucleic acid (mRNA) between 1.5-and 2-fold. The time-response profile of the induction of aromatase activity and CYP19 mRNA by the triazines was similar to that by 8-bromo-cyclic adenosine monophosphate, a known stimulant of the protein kinase-A pathway that mediates the induction of aromatase in these cells. The observed induction of aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, may be an underlying explanation for some of the reported hormonal disrupting and tumor promoting properties of these herbicides in vivo. Key Words: aromatase; atrazine; simazine; propazine; triazines; induction; adrenocortical carcinoma; CYP19; mRNA. In recent years, there has been growing concern that certain environmental contaminants and commercial products have the potential to disturb endocrine functions in exposed humans and wildlife. Disturbances by these "endocrine disrupters" may lead to impaired reproductive capacity and other toxicities related to sexual differentiation, growth, and development. Current research has focused on potential interactions with the sex hormone receptors, particularly the estrogen receptor The H295 and H295R (a subpopulation of H295 that forms a monolayer in culture) human adrenocortical carcinoma cell lines have been characterized in detail and shown to express most of the key enzymes necessary for steroidogenesis The triazine family of broad-leaved herbicides has been used increasingly since the 1960s to control weeds, particularly in maize crops, in North America and Europe. The estimated use 1 To whom correspondence should be addressed. Fax: 011-31-30 -253-5077. E-mail: [email protected]. TOXICOLOGICAL SCIENCES 54, 121-127 (2000) Copyright © 2000 by the Society of Toxicology 121 of atrazine in the United States was almost 35,000 tons in 1993 (U.S. MATERIALS AND METHODS Cell culture conditions. H295R cells were obtained from the American Type Culture Collection (ATCC # CRL-2128) and grown in 75-cm 2 flasks (Greiner, Germany) under culture conditions published previously Isolation and amplification of RNA. RNA was isolated using the RNA Insta-Pure System (Eurogentec, Belgium) according to the manufacturerЈs instructions and stored at -70°C. RT-PCRs were performed using the Access RT-PCR System (Promega, U.S.). Northern blotting was not considered as an option because of the low basal expression of aromatase, which could not be detected by other investigators using this technique Aromatase assay. The catalytic activity of aromatase was determined based on the method of RESULT

Heterogeneous antimicrobial activity in broncho-alveolar aspirates from mechanically ventilated intensive care unit patients

Pneumonia is an infection of the lungs, where the alveoli in the affected area are filled with pus and fluid. Although ventilated patients are at risk, not all ventilated patients develop pneumonia. This suggests that the sputum environment may possess antimicrobial activities. Despite the generally acknowledged importance of antimicrobial activity in protecting the human lung against infections, this has not been systematically assessed to date. Therefore, the objective of the present study was to measure antimicrobial activity in broncho-alveolar aspirate ('sputum") samples from patients in an intensive care unit (ICU) and to correlate the detected antimicrobial activity with antibiotic levels, the sputum microbiome, and the respective patients' characteristics. To this end, clinical metadata and sputum were collected from 53 mechanically ventilated ICU patients. The antimicrobial activity of sputum samples was tested against Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus anginosus. Here we show that sputa collected from different patients presented a high degree of variation in antimicrobial activity, which can be partially attributed to antibiotic therapy. The sputum microbiome, although potentially capable of producing antimicrobial agents, seemed to contribute in a minor way, if any, to the antimicrobial activity of sputum. Remarkably, despite its potentially protective effect, the level of antimicrobial activity in the investigated sputa correlated inversely with patient outcome, most likely because disease severity outweighed the beneficial antimicrobial activities.</p

Alkaline phosphatase: An old enzyme newly discovered as a medicine

Alkaline phosphatase (AP), a non-toxic natural compound (enzyme) has a great potential to replace or avoid the use of various drugs, in particular anti-inflammatory drugs (e.g. used during surgery and to reduce arthritis) and antibiotics applied to farm animals, which both have serious negative effects on the environment. Promising studies are being performed to demonstrate the possibility to avoid complications after major surgery (thereby eliminating the need to use harmful drugs for many years) and the reduction of antibiotics use in piglets

Alkaline phosphatase: An old enzyme newly discovered as a medicine

Alkaline phosphatase (AP), a non-toxic natural compound (enzyme) has a great potential to replace or avoid the use of various drugs, in particular anti-inflammatory drugs (e.g. used during surgery and to reduce arthritis) and antibiotics applied to farm animals, which both have serious negative effects on the environment. Promising studies are being performed to demonstrate the possibility to avoid complications after major surgery (thereby eliminating the need to use harmful drugs for many years) and the reduction of antibiotics use in piglets