Melatonin counteracts lipid peroxidation induced by carbon tetrachloride but does not restore glucose-6 phosphatase activity

Abstract: Carbon tetrachloride (CC1₄) exerts its toxic effects by the generation of free radicals. In this study we investigated whether melatonin, a potent free radical scavenger, could prevent the deleterious effects of CC1₄. Liver homogenates and liver microsomes were incubated with CCI4 in the presence of melatonin and lipid peroxidation and glucose-6 phosphatase (G6Pase) activity were determined. All doses of CC1₄ (1, 0.5, 0.1 raM) produced significantly high levels of lipid peroxidation, as reflected by increased levels of malonaldehyde and 4-hydroxyalkenals, in both liver homogenates and liver microsomes. These doses of CC1₄ concommitantly reduced the activity of microsomal G6Pase. Co-incubation with melatonin dose-dependently (2, 1, 0.5 raM) inhibited the production of lipid peroxidation, but it was unable to restore the activity of G6Pase. In in vivo studies, rats were also treated with melatonin (10 mg/kg, i.p.), given 30 min before and 60 min after the administration of CC1₄ (5 ml/kg, i.p.). Significantly elevated levels of lipid peroxidation were measured in the liver and kidney. Melatonin prevented the CCl₄-induced lipid peroxidation in the kidney, but not in the liver. These data suggest that melatonin may provide protection against some of the damaging effects of CCI4, possibly due to its ability to scavenge toxic free radicals.     

Treatment of experimental myocarditis via modulation of the renin-angiotensin system

The renin-angiotensin system is primarily responsible for regulating vascular tone. Drugs that inhibit this pathway, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, are widely used to treat hypertension and a variety of cardiomyopathies. Recent studies have shown that, in addition to reducing blood pressure, these drugs also modulate inflammation, adhesion molecule expression, and fibrosis. To assess the therapeutic potential of these inhibitory agents for the treatment of inflammatory heart disease, the drugs have been tested in experimental models of infectious and autoimmune myocarditis. This review summarizes the results of studies examining the efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists for the treatment of mouse models of virus-induced and parasite-induced myocarditis, as well as autoimmune cardiomyopathy. The collective results strongly support the use of renin-angiotensin modulation for the treatment of myocarditis. Importantly, this therapeutic approach seems to downregulate autoimmunity without causing immune suppression which may enhance the survival of the disease-initiating infectious agent.     

Autophagic dysfunction in mucolipidosis type IV patients

Mutations in Mucolipin 1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by several neurological and ophthalmological abnormalities. It has been proposed that MCOLN1 might regulate transport of membrane components in the late endosomal-lysosomal pathway; however, the mechanisms by which defects of MCOLN1 function result in mental and psychomotor retardation remain largely unknown. In this study, we show constitutive activation of autophagy in fibroblasts obtained from MLIV patients. Accumulation of autophagosomes in MLIV cells was due to the increased de novo autophagosome formation and to delayed fusion of autophagosomes with late endosomes/lysosomes. Impairment of the autophagic pathway led to increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitin proteins may contribute to the neurodegeneration observed in MLIV patients. In addition, we found that delivery of platelet-derived growth factor receptor to lysosomes is delayed in MCOLN1-deficient cells, suggesting that MCOLN1 is necessary for efficient fusion of both autophagosomes and late endosomes with lysosomes. Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders.     

HIV testing rates among African Americans: why are they not increasing?

HIV/AIDS disproportionately affects the African-American community. It is imperative to increase the awareness of HIV/AIDS as well as the amount of people getting tested. Sometimes strategies to increase testing in the African-American community do not have to do with access but more so with other circumstances surrounding testing. These include fear of needles, being discriminated against if HIV-positive, perception of low risk, and long waiting periods for results. It is important to consider that all of these factors have an effect on peoples' decision to be tested for HIV/AIDS when offering testing.     

Within-day drinking water consumption patterns: results from a drinking water consumption survey

Data currently available on drinking water intakes do not support dietary exposure estimates for contaminants that have acute effects lasting less than 24 h. Realistic exposure estimates for these types of contaminants in drinking water require detailed information on amounts and time of consumption for each drinking occasion during a day. A nationwide water consumption survey was conducted to address how often, when, and how much water is consumed at specific times during the day. The survey was conducted in two waves, to represent two seasons, and the survey instrument consisted of 7-day water consumption diaries. Data on total daily amounts consumed, number of drinking occasions per day, amounts consumed per drinking occasion, and intervals between drinking occasions show larger between-subjects variation than within-subject variation. Statistically significant associations were also observed between drinking water consumption patterns and participants' ages and sex and geographical regions in which these participants live. The number of drinking occasions on a given day varied from 0 to 19, with the majority of respondents reporting 6 or less drinking occasions per day. The average interval between drinking occasions varied from 1 to 17 h, with 57% of the person-days reporting average intervals at least 3 h apart. The mean amount consumed per drinking occasion showed little association with the number of drinking occasions and fluctuated between 8 and 10 oz. To our knowledge, this survey is the only source of information on within-day patterns (i.e., when and how much) of drinking water consumption for a nationally representative sample of the US population. The detailed water consumption data from this survey can be used to support less than 24-h dietary exposure estimates for contaminants in drinking water.     

Prenatal Phthalate Exposures and Childhood Fat Mass in a New York City Cohort

Background:

Experimental animal studies and limited epidemiologic evidence suggest that prenatal exposure to phthalates may be obesogenic, with potential sex-specific effects of phthalates having anti-androgenic activity.

Objectives:

We aimed to assess associations between prenatal phthalate exposures and childhood fat mass in a prospective cohort study.

Methods:

We measured phthalate metabolite concentrations in third-trimester maternal urine in a cohort of women enrolled in New York City between 1998 and 2002 (n = 404). Among 180 children (82 girls and 98 boys), we evaluated body composition using a Tanita scale at multiple follow-up visits between ages 4 and 9 years (363 total visits). We estimated associations of standard deviation differences or tertiles of natural log phthalate metabolite concentrations with percent fat mass using linear mixed-effects regression models with random intercepts for repeated outcome measurements. We assessed associations in multiple metabolite models and adjusted for covariates including prepregnancy body mass index, gestational weight gain, maternal smoking during pregnancy, and breastfeeding.

Results:

We did not observe associations between maternal urinary phthalate concentrations and percent body fat in models examining continuous exposures. Fat mass was 3.06% (95% CI: –5.99, –0.09%) lower among children in the highest tertile of maternal urinary concentrations of summed di(2-ethylhexyl) phthalate (ΣDEHP) metabolites than in children in the lowest tertile. Though estimates were imprecise, there was little evidence that associations between maternal urinary phthalate concentrations and percent fat mass were modified by child’s sex.

Conclusions:

Prenatal phthalate exposures were not associated with increased body fat among children 4–9 years of age, though high prenatal DEHP exposure may be associated with lower fat mass in childhood.

Citation:

Buckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, Wolff MS, Herring AH. 2016. Prenatal phthalate exposures and childhood fat mass in a New York City cohort. Environ Health Perspect 124:507–513; http://dx.doi.org/10.1289/ehp.1509788     

Molecular requirements for inhibition of the chemokine receptor CCR8 – probe-dependent allosteric interactions

BACKGROUND AND PURPOSE

Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.

EXPERIMENTAL APPROACH

The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gα_i signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148.

KEY RESULTS

All compounds were highly potent inverse agonists with EC₅₀ values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC₅₀ values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [¹²⁵I]-CCL1 (K_i 3.4–842 nM), whereas the affinities measured against [¹²⁵I]-MC148 were less widely spread (K_i 0.37–27 nM), and matched the inverse agonist potencies.

CONCLUSION AND IMPLICATIONS

Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties.     

Kaposi's sarcoma in AIDS: basement membrane and endothelial cell markers in late-stage lesions

Early-stage lesions of Kaposi's sarcoma (KS) are composed of single-layered, highly flattened cells lining collagen bundles, whereas late-stage lesions contain densely packed, spindle-shaped cells. We examined the progression of KS lesions in oral mucosa and lymph nodes from patients with AIDS, using antibodies specific for blood vascular endothelial cells (Factor VIII-related antigen) and their basement membrane (Type IV collagen and laminin). In addition, the plant lectin Ulex europaeus, which selectively stains blood vessels, was also used. In early-stage KS lesions, fibronectin, laminin and Type IV collagen were co-distributed at the interface between KS cells and collagen bundles; Factor VIII-related antigen and Ulex europaeus lectin staining was present in vascular channels and in the KS cells. However, in late-stage lesions, few if any KS cells stained with antibody to Factor VIII-associated antigen, although endothelial cells lining blood vessels were positive. Strong staining for laminin and Type IV collagen was present in a pericellular pattern throughout the nodular late-stage lesions. Since lymphatic capillary endothelium does not produce basement-membrane-specific macromolecules, these results support the conclusion that KS cells are related to blood vascular endothelium but eventually lose certain endothelium-specific markers as the cells are transformed into the spindle-shaped cell type.     

颈动脉内膜剥脱术后即期脑中风的病因、影响因素及治疗（摘要）

对２９１例颈动脉内膜剥脱术后患者进行随访研究，１例术后即期死亡；２２例（６．３％）在术后发生脑中风，１７例为中度中风，５例为严重中风，即期中风的病因包括：１４例手术部位颈动脉血栓形成（１４／２２，６４％），４例术中或术后即期脑栓塞，２例阻断颈动脉所致脑缺血，１例脑出血，１例原因不明，此外讨论了术后中风的危险因素和处理方法。     

Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST)

Pathogenetic pathways of gastrointestinal stromal tumors (GIST) lacking mutations in KIT and PDGFRA (∼15%) are still poorly studied. Nearly nothing is known about PI3K alterations in GISTs and only a few GISTs with BRAF mutations have been reported. BRAF mutations (V600E) were found in 3/87 tumors (3.5%) concomitantly were wild type for KIT and PDGFRA. No mutations were detected in KRAS, NRAS, and FGFR3. For the first-time we demonstrated a PIK3CA mutation (H1047L) simultaneously occurring with a 15-bp deletion in KIT exon 11 in one tumor. We suggest that BRAF mutations are of pathogenetic significance in wild type GISTs. The PI3K pathway should be assessed in future studies.