Hepatic fibrogenesis requires sympathetic neurotransmitters

Background and aims: Hepatic stellate cells (HSC) are activated by liver injury to become proliferative fibrogenic myofibroblasts. This process may be regulated by the sympathetic nervous system (SNS) but the mechanisms involved are unclear. Methods: We studied cultured HSC and intact mice with liver injury to test the hypothesis that HSC respond to and produce SNS neurotransmitters to promote fibrogenesis. Results: HSC expressed adrenoceptors, catecholamine biosynthetic enzymes, released norepinephrine (NE), and were growth inhibited by α- and β-adrenoceptor antagonists. HSC from dopamine β-hydroxylase deficient (Dbh(−/−)) mice, which cannot make NE, grew poorly in culture and were rescued by NE. Inhibitor studies demonstrated that this effect was mediated via G protein coupled adrenoceptors, mitogen activated kinases, and phosphatidylinositol 3-kinase. Injury related fibrogenic responses were inhibited in Dbh(−/−) mice, as evidenced by reduced hepatic accumulation of α-smooth muscle actin(+ve) HSC and decreased induction of transforming growth factor β1 (TGF-β1) and collagen. Treatment with isoprenaline rescued HSC activation. HSC were also reduced in leptin deficient ob/ob mice which have reduced NE levels and are resistant to hepatic fibrosis. Treating ob/ob mice with NE induced HSC proliferation, upregulated hepatic TGF-β1 and collagen, and increased liver fibrosis. Conclusions: HSC are hepatic neuroglia that produce and respond to SNS neurotransmitters to promote hepatic fibrosis

The effects of ProAlgaZyme novel algae infusion on metabolic syndrome and markers of cardiovascular health

<p>Abstract</p> <p>Background</p> <p>Metabolic Syndrome, or Syndrome X, is characterized by a set of metabolic and lipid imbalances that greatly increases the risk of developing diabetes and cardiovascular disease. The syndrome is highly prevalent in the United States and worldwide, and treatments are in high demand. ProAlgaZyme, a novel and proprietary freshwater algae infusion in purified water, has been the subject of several animal studies and has demonstrated low toxicity even with chronic administration at elevated doses. The infusion has been used historically for the treatment of several inflammatory and immune disorders in humans and is considered well-tolerated. Here, the infusion is evaluated for its effects on the cardiovascular risk factors present in metabolic syndrome in a randomized double-blind placebo-controlled study involving 60 overweight and obese persons, ages 25–60. All participants received four daily oral doses (1 fl oz) of ProAlgaZyme (N = 22) or water placebo (N = 30) for a total of 10 weeks, and were encouraged to maintain their normal levels of physical activity. Blood sampling and anthropometric measurements were taken at the beginning of the study period and after 4, 8 and 10 weeks of treatment. Eight participants did not complete the study.</p> <p>Results</p> <p>ProAlgaZyme brought about statistically significant (p < 0.001) reductions in the following: weight, body fat, total cholesterol, LDL-cholesterol, triglycerides, C-reactive protein and fasting blood glucose levels, accompanied by a significant (p < 0.001) increase in HDL-cholesterol levels over the 10-week study period. The infusion was well-tolerated and no side effects were noted.</p> <p>Conclusion</p> <p>ProAlgaZyme (4 fl oz daily) consumption resulted in significant reductions in weight and blood glucose levels, while significantly improving serum lipid profiles and reducing markers of inflammation, thus improving cardiovascular risk factors in overweight and obese subjects over a course of 10 weeks with an absence of adverse side effects.</p> <p>Trial Registration</p> <p>US ClinicalTrials.gov NCT00489333</p

Care standards for non-alcoholic fatty liver disease in the United Kingdom 2016: a cross-sectional survey

OBJECTIVE: Guidelines for the assessment of non-alcoholic fatty liver disease (NAFLD) have been published in 2016 by National Institute for Health and Care Excellence and European Associations for the study of the Liver-European Association for the study of Diabetes-European Association for the study of Obesity. Prior to publication of these guidelines, we performed a cross-sectional survey of gastroenterologists and hepatologists regarding NAFLD diagnosis and management. DESIGN: An online survey was circulated to members of British Association for the Study of the Liver and British Society of Gastroenterology between February 2016 and May 2016. RESULTS: 175 gastroenterologists/hepatologists responded, 116 completing the survey, representing 84 UK centres. 22% had local NAFLD guidelines. 45% received >300 referrals per year from primary care for investigation of abnormal liver function tests (LFTs). Clinical assessment tended to be performed in secondary rather than primary care including body mass index (82% vs 26%) and non-invasive liver screen (86% vs 32%) and ultrasound (81% vs 37%). Widely used tools for non-invasive fibrosis risk stratification were aspartate transaminase (AST)/alanine transaminase (ALT) ratio (53%), Fibroscan (50%) and NAFLD fibrosis score (41%). 78% considered liver biopsy in selected cases. 50% recommended 10% weight loss target as first-line treatment. Delivery of lifestyle interventions was mostly handed back to primary care (56%). A minority have direct access to community weight management services (22%). Follow-up was favoured by F3/4 fibrosis (72.9%), and high-risk non-invasive fibrosis tests (51%). Discharge was favoured by simple steatosis at biopsy (30%), and low-risk non-invasive scores (25%). CONCLUSIONS: The survey highlights areas for improvement of service provision for NAFLD assessment including improved recognition of non-alcoholic steatohepatitis in people with type 2 diabetes, streamlining abnormal LFT referral pathways, defining non-invasive liver fibrosis assessment tools, use of liver biopsy, managing metabolic syndrome features and improved access to lifestyle interventions

Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity

We investigated the regulation of hepatic ER stress in healthy liver and adult or perinatally programmed diet-induced non-alcoholic fatty liver disease (NAFLD). Female mice were fed either obesogenic or control diet before mating, during pregnancy and lactation. Post-weaning, offspring from each maternal group were divided into either obesogenic or control diet. At six months, offspring were sacrificed at 4-h intervals over 24 h. Offspring fed obesogenic diets developed NAFLD phenotype, and the combination of maternal and offspring obesogenic diets exacerbated this phenotype. UPR signalling pathways (IREα, PERK, ATF6) and their downstream regulators showed different basal rhythmicity, which was modified in offspring exposed to obesogenic diet and maternal programming. The double obesogenic hit increased liver apoptosis measured by TUNEL staining, active caspase-3 and phospho-JNK and GRP78 promoter methylation levels. This study demonstrates that hepatic UPR is rhythmically activated. The combination of maternal obesity (MO) and obesogenic diets in offspring triggered altered UPR rhythmicity, DNA methylation and cellular apoptosis

Child Poverty Monitor: Technical Report 2017

The Child Poverty Monitor and this Technical Report provide data on a set of indicators that assess aspects of child poverty in New Zealand and their implications for child wellbeing. In it are data on income and non-income measures of poverty, including measures that reflect increasing levels of severity. Other data include indicators related to health, living conditions, education, and a selection of economic measures used to assess how well we are doing as a nation that are relevant to the wellbeing of children and their families. The Child Poverty Monitor is a partnership comprising the Office of the Children’s Commissioner, the University of Otago’s New Zealand Child and Youth Epidemiology Service (NZCYES) and the J R McKenzie Trust. The purpose is to compile and share robust information on child poverty measures that are publicly available and easily accessible. Only by having the essential measures on child poverty in New Zealand compiled, published and disseminated annually can we tell how well we are progressing in effectively reducing child poverty in our nation

Influence of the initial chemical conditions on the rational design of silica particles

The influence of the water content in the initial composition on the size of silica particles produced using the Stöber process is well known. We have shown that there are three morphological regimes defined by compositional boundaries. At low water levels (below stoichiometric ratio of water:tetraethoxysilane), very high surface area and aggregated structures are formed; at high water content (>40 wt%) similar structures are also seen. Between these two boundary conditions, discrete particles are formed whose size are dictated by the water content. Within the compositional regime that enables the classical Stöber silica, the structural evolution shows a more rapid attainment of final particle size than the rate of formation of silica supporting the monomer addition hypothesis. The clearer understanding of the role of the initial composition on the output of this synthesis method will be of considerable use for the establishment of reliable reproducible silica production for future industrial adoption

Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-Cell Chronic Lymphocytic Leukemia

Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eµ-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in Eμ-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)–approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors

Oxidative Stress-Induced JNK/AP-1 Signaling is a Major Pathway Involved in Selective Apoptosis of Myelodysplastic Syndrome Cells by Withaferin-A

Myelodysplastic syndromes (MDS) are a diverse group of malignant clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology in one or more hematopoietic lineages, and a risk of progression to acute myeloid leukemia (AML). Approximately 50% of MDS patients respond to current FDA-approved drug therapies but a majority of responders relapse within 2-3 years. There is therefore a compelling need to identify potential new therapies for MDS treatment. We utilized the MDS-L cell line to investigate the anticancer potential and mechanisms of action of a plant-derived compound, Withaferin A (WFA), in MDS. WFA was potently cytotoxic to MDS-L cells but had no significant effect on the viability of normal human primary bone marrow cells. WFA also significantly reduced engraftment of MDS-L cells in a xenotransplantation model. Through transcriptome analysis, we identified reactive oxygen species (ROS)-activated JNK/AP-1 signaling as a major pathway mediating apoptosis of MDS-L cells by WFA. We conclude that the molecular mechanism mediating selective cytotoxicity of WFA on MDS-L cells is strongly associated with induction of ROS. Therefore, pharmacologic manipulation of redox biology could be exploited as a selective therapeutic target in MDS

Evidence-based assessment of antiosteoporotic activity of petroleum-ether extract of Cissus quadrangularis Linn. on ovariectomy-induced osteoporosis

The increasing incidence of postmenopausal osteoporosis and its related fractures have become global health issues in the recent days. Postmenopausal osteoporosis is the most frequent metabolic bone disease; it is characterized by a rapid loss of mineralized bone tissue. Hormone replacement therapy has proven efficacious in preventing bone loss but not desirable to many women due to its side-effects. Therefore we are in need to search the natural compounds for a treatment of postmenopausal symptoms in women with no toxic effects. In the present study, we have evaluated the effect of petroleum-ether extract of Cissus quadrangularis Linn. (CQ), a plant used in folk medicine, on an osteoporotic rat model developed by ovariectomy. In this experiment, healthy female Wistar rats were divided into four groups of six animals each. Group 1 was sham operated. All the remaining groups were ovariectomized. Group 2 was fed with an equivolume of saline and served as ovariectomized control (OVX). Groups 3 and 4 were orally treated with raloxifene (5.4 mg/kg) and petroleum-ether extract of CQ (500 mg/kg), respectively, for 3 months. The findings were assessed on the basis of animal weight, morphology of femur, and histochemical localization of alkaline phosphatase (ALP) (an osteoblastic marker) and tartrate-resistant acid phosphatase (TRAP) (an osteoclastic marker) in upper end of femur. The study revealed for the first time that the petroleum-ether extract of CQ reduced bone loss, as evidenced by the weight gain in femur, and also reduced the osteoclastic activity there by facilitating bone formation when compared to the OVX group. The osteoclastic activity was confirmed by TRAP staining, and the bone formation was assessed by ALP staining in the femur sections. The color intensity of TRAP and ALP enzymes from the images were evaluated by image analysis software developed locally. The effect of CQ was found to be effective on both enzymes, and it might be a potential candidate for prevention and treatment of postmenopausal osteoporosis. The biological activity of CQ on bone may be attributed to the phytogenic steroids present in it