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101.
Omega-3 fatty acids and metabolic syndrome: Effects and emerging mechanisms of action 总被引:1,自引:0,他引:1
Hemant Poudyal Sunil K. Panchal Vishal Diwan Lindsay Brown 《Progress in lipid research》2011,50(4):372-387
Epidemiological, human, animal, and cell culture studies show that n−3 fatty acids, especially α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), reduce the risk factors of cardiovascular diseases. EPA and DHA, rather than ALA, have been the focus of research on the n−3 fatty acids, probably due to the relatively inefficient conversion of ALA to EPA and DHA in rodents and humans. This review will assess our current understanding of the effects and potential mechanisms of actions of individual n−3 fatty acids on multiple risk factors of metabolic syndrome. Evidence for pharmacological responses and the mechanism of action of each of the n−3 fatty acid trio will be discussed for the major risk factors of metabolic syndrome, especially adiposity, dyslipidemia, insulin resistance and diabetes, hypertension, oxidative stress, and inflammation. Metabolism of n−3 and n−6 fatty acids as well as the interactions of n−3 fatty acids with nutrients, gene expression, and disease states will be addressed to provide a rationale for the use of n−3 fatty acids to reduce the risk factors of metabolic syndrome. 相似文献
102.
Tony D'Amore Chandra J. Panchal Inge Russeil Graham G. Stewart 《Journal of industrial microbiology & biotechnology》1988,2(6):365-372
Summary The intracellular accumulation of ethanol in yeast and its potential effects on growth and fermentation have been topics of controversy for the past several years. The determination of intracellular ethanol based on the exclusion of [14C]sorbitol to estimate aqueous cell volume was used to examine the question of intracellular ethanol accumulation. An intracellular accumulation of ethanol inSaccharomyces cerevisiae was observed during the early stages of fermentation. However, as fermentation continued, the intracellular and extracellular concentrations of ethanol became similar. Increasing the osmotic pressure of the medium with glucose or sorbitol was observed to cause an increase in the intracellular ethanol concentration. Associated with this was a decrease in yeast growth and fermentation rates. In addition, increasing the osmotic pressure of the medium was observed to cause an increase in glycerol production. Supplementation of the media with excess peptone, yeast extract, magnesium sulfate and potassium phosphate was found to relieve the detrimental effects of high osmotic pressure. Under these conditions, though, no effect on the intracellular and extracellular ethanol distribution was observed. These results indicate that nutrient limitation, and not necessarily intracellular ethanol accumulation, plays a key role during yeast fermentations in media of high osmolarity. 相似文献
103.
Kinariwala Dhvany Panchal Gauravkumar Sakure Amar Hati Subrota 《International journal of peptide research and therapeutics》2020,26(3):1613-1627
International Journal of Peptide Research and Therapeutics - In the study, ten different Lactobacillus cultures were considered for the study of ɑ-amylase, ɑ-glucosidase and pancreatic... 相似文献
104.
Nick Bailey Mark J. Bamford Delphine Brissy Joanna Brookfield Emmanuel Demont Richard Elliott Neil Garton Irene Farre-Gutierrez Thomas Hayhow Gail Hutley Antoinette Naylor Terry A. Panchal Hui-Xian Seow David Spalding Andrew K. Takle 《Bioorganic & medicinal chemistry letters》2009,19(13):3602-3606
Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties. 相似文献
105.
Krishna P. Kota Brett Eaton Douglas Lane Melanie Ulrich Ricky Ulrich Brian D. Peyser Camenzind G. Robinson James G. Jaissle Gianluca Pegoraro Sina Bavari Rekha G. Panchal 《PloS one》2013,8(1)
The molecular machinery that regulates the entry and survival of Yersinia pestis in host macrophages is poorly understood. Here, we report the development of automated high-content imaging assays to quantitate the internalization of virulent Y. pestis CO92 by macrophages and the subsequent activation of host NF-κB. Implementation of these assays in a focused chemical screen identified kinase inhibitors that inhibited both of these processes. Rac-2-ethoxy-3 octadecanamido-1-propylphosphocholine (a protein Kinase C inhibitor), wortmannin (a PI3K inhibitor), and parthenolide (an IκB kinase inhibitor), inhibited pathogen-induced NF-κB activation and reduced bacterial entry and survival within macrophages. Parthenolide inhibited NF-κB activation in response to stimulation with Pam3CSK4 (a TLR2 agonist), E. coli LPS (a TLR4 agonist) or Y. pestis infection, while the PI3K and PKC inhibitors were selective only for Y. pestis infection. Together, our results suggest that phagocytosis is the major stimulus for NF-κB activation in response to Y. pestis infection, and that Y. pestis entry into macrophages may involve the participation of protein kinases such as PI3K and PKC. More importantly, the automated image-based screening platform described here can be applied to the study of other bacteria in general and, in combination with chemical genetic screening, can be used to identify host cell functions facilitating the identification of novel antibacterial therapeutics. 相似文献
106.
Hemant Poudyal Sunil K. Panchal Leigh C. Ward Lindsay Brown 《The Journal of nutritional biochemistry》2013,24(6):1041-1052
We compared the cardiovascular, hepatic and metabolic responses to individual dietary n-3 fatty acids (α-linolenic acid, ALA; eicosapentaenoic acid, EPA; and docosahexaenoic acid, DHA) in a high-carbohydrate, high-fat diet-induced model of metabolic syndrome in rats. Additionally, we measured fatty acid composition of plasma, adipose tissue, liver, heart and skeletal muscle in these rats. The same dosages of ALA and EPA/DHA produced different physiological responses to decrease the risk factors for metabolic syndrome. ALA did not reduce total body fat but induced lipid redistribution away from the abdominal area and favorably improved glucose tolerance, insulin sensitivity, dyslipidemia, hypertension and left ventricular dimensions, contractility, volumes and stiffness. EPA and DHA increased sympathetic activation, reduced the abdominal adiposity and total body fat and attenuated insulin sensitivity, dyslipidemia, hypertension and left ventricular stiffness but not glucose tolerance. However, ALA, EPA and DHA all reduced inflammation in both the heart and the liver, cardiac fibrosis and hepatic steatosis. These effects were associated with complete suppression of stearoyl-CoA desaturase 1 activity. Since the physiological responses to EPA and DHA were similar, it is likely that the effects are mediated by DHA with EPA serving as a precursor. Also, ALA supplementation increased DHA concentrations but induced different physiological responses to EPA and DHA. This result strongly suggests that ALA has independent effects in metabolic syndrome, not relying on its metabolism to DHA. 相似文献
107.
Lacroix C Giovannini D Combe A Bargieri DY Späth S Panchal D Tawk L Thiberge S Carvalho TG Barale JC Bhanot P Ménard R 《Nature protocols》2011,6(9):1412-1428
We describe here a highly efficient procedure for conditional mutagenesis in Plasmodium. The procedure uses the site-specific recombination FLP-FRT system of yeast and targets the pre-erythrocytic stages of the rodent Plasmodium parasite P. berghei, including the sporozoite stage and the subsequent liver stage. The technique consists of replacing the gene under study by an FRTed copy (i.e., flanked by FRT sites) in the erythrocytic stages of a parasite clone that expresses the flip (FLP) recombinase stage-specifically--called the 'deleter' clone. We present the available deleter clones, which express FLP at different times of the parasite life cycle, as well as the schemes and tools for constructing new deleter parasites. We also outline and discuss the various strategies for exchanging a wild-type gene with an FRTed copy and for generating conditional gene knockout or knockdown parasite clones. Finally, we detail the protocol for obtaining sporozoites that lack a protein of interest and for monitoring sporozoite-specific DNA excision and depletion of the target protein. The protocol should allow the functional analysis of any essential protein in the sporozoite, liver stage or hepatic merozoite stages of rodent Plasmodium parasites. 相似文献
108.
Lisa Leung Nikolina Radulovich Chang-Qi Zhu Shawna Organ Bizhan Bandarchi Melania Pintilie Christine To Devang Panchal Ming Sound Tsao 《PloS one》2012,7(10)
Lipocalin 2 (LCN2) is a small secreted protein and its elevated expression has been observed in pancreatic as well as other cancer types. LCN2 has been reported to promote resistance to drug-induced apoptosis, enhance invasion through its physical association with matrix metalloproteinase-9, and promote in vivo tumor growth. LCN2 was found to be commonly expressed in patient PDAC samples and its pattern of immunohistochemical staining intensified with increasing severity in high-grade precursor lesions. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high LCN2 expression significantly reduced attachment, invasion, and tumour growth in vivo, but not proliferation or motility. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high expression significantly reduced attachment, invasion, and tumour growth in vivo. In contrast, LCN2 overexpression in PANC1, with low endogenous expression, significantly increased invasion, attachment, and enhanced tumor growth. Suppression of LCN2 in BxPC3 and HPAF-II cells increased their sensitivity to gemcitabine in vitro, and in vivo when BxPC3 was tested. Furthermore, LCN2 promotes expression of VEGF and HIF1A which contribute to enhanced vascularity. These overall results demonstrate that LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma and is a potential therapeutic target for this disease. 相似文献
109.
Poudyal H Panchal SK Ward LC Waanders J Brown L 《American journal of physiology. Endocrinology and metabolism》2012,302(12):E1472-E1482
Age-related physiological changes develop at the same time as the increase in metabolic syndrome in humans after young adulthood. There is a paucity of data in models mimicking chronic diet-induced changes in human middle age and interventions to reverse these changes. This study measured the changes during chronic consumption of a high-carbohydrate (as cornstarch), low-fat (C) diet and a high-carbohydrate (as fructose and sucrose), high-fat (H) diet in rats for 32 wk. C diet feeding induced changes without metabolic syndrome, such as disproportionate increases in total body lean and fat mass, reduced bone mineral content, cardiovascular remodeling with increased systolic blood pressure, left ventricular and arterial stiffness, and increased plasma markers of liver injury. H diet feeding induced visceral adiposity with reduced lean mass, increased lipid infiltration in the skeletal muscle, impaired glucose and insulin tolerance, cardiovascular remodeling, hepatic steatosis, and increased infiltration of inflammatory cells in the heart and the liver. Chia seed supplementation for 24 wk attenuated most structural and functional modifications induced by age or H diet, including increased whole body lean mass and lipid redistribution from the abdominal area, and normalized the chronic low-grade inflammation induced by H diet feeding; these effects may be mediated by increased metabolism of anti-inflammatory n-3 fatty acids from chia seed. These results suggest that chronic H diet feeding for 32 wk mimics the diet-induced cardiovascular and metabolic changes in middle age and that chia seed may serve as an alternative dietary strategy in the management of these changes. 相似文献
110.
Rekha G. Panchal Ricky L. Ulrich Steven B. Bradfute Douglas Lane Gordon Ruthel Tara A. Kenny Patrick L. Iversen Arthur O. Anderson Rick Gussio William C. Raschke Sina Bavari 《The Journal of biological chemistry》2009,284(19):12874-12885
The modulation of cellular processes by small molecule inhibitors, gene
inactivation, or targeted knockdown strategies combined with phenotypic
screens are powerful approaches to delineate complex cellular pathways and to
identify key players involved in disease pathogenesis. Using chemical genetic
screening, we tested a library of known phosphatase inhibitors and identified
several compounds that protected Bacillus anthracis infected
macrophages from cell death. The most potent compound was assayed against a
panel of sixteen different phosphatases of which CD45 was found to be most
sensitive to inhibition. Testing of a known CD45 inhibitor and antisense
phosphorodiamidate morpholino oligomers targeting CD45 also protected B.
anthracis-infected macrophages from cell death. However, reduced CD45
expression did not protect anthrax lethal toxin (LT) treated macrophages,
suggesting that the pathogen and independently added LT may signal through
distinct pathways. Subsequent, in vivo studies with both
gene-targeted knockdown of CD45 and genetically engineered mice expressing
reduced levels of CD45 resulted in protection of mice after infection with the
virulent Ames B. anthracis. Intermediate levels of CD45 expression
were critical for the protection, as mice expressing normal levels of CD45 or
disrupted CD45 phosphatase activity or no CD45 all succumbed to this pathogen.
Mechanism-based studies suggest that the protection provided by reduced CD45
levels results from regulated immune cell homeostasis that may diminish the
impact of apoptosis during the infection. To date, this is the first report
demonstrating that reduced levels of host phosphatase CD45 modulate anthrax
pathogenesis.Interactions between microbes and immune cells play a critical role in
microbial pathogenesis. Many pathogenic organisms exploit the host immune
machinery and subsequently modulate cell function, signaling, migration, and
cytoskeleton rearrangement. Hence, identifying host cellular components with
which microbes interact will allow for a more comprehensive understanding of
microbial pathogenesis, define common strategies used by multiple pathogens,
and elucidate unique tactics evolved by individual species to help establish
infections or evade host innate responses. Another interesting aspect of
infection is that diverse pathogens seem to target common cellular pathways
(1,
2). Thus, identifying host
targets exploited by multiple pathogens will be useful in the development of
broad-spectrum host-oriented therapeutics and vaccines.Protein kinases and phosphatases regulate a range of cellular responses to
external and internal stimuli, including cell proliferation, metabolism, and
apoptosis. Aberrant kinase and/or phosphatase activities underlie many
different types of pathological conditions from cancer to infectious diseases.
Protein kinases have been extensively investigated as targets for drug
discovery. In addition, phosphatases are now being recognized as important
regulators of many biological processes. In particular, there is an increasing
interest in protein-tyrosine phosphatases
(PTPs)3 as drug
targets
(3–8)
because immune cells express a remarkably high proportion of the 107 PTP genes
in the human genome (9) and
also due to the growing number of human diseases discovered to be associated
with PTP abnormalities
(9–11).
The involvement of cellular and bacterial PTPs during intracellular microbial
pathogenesis has been a topic of significant interest
(2,
12,
13). The bacterial PTP YopH,
secreted by Yersinia pestis, interferes with the host
adhesion-regulated signaling pathway via dephosphorylation of selective
tyrosine-phosphorylated proteins
(14). Activation of host PTPs
after infection with bacteria or their virulence factors has been demonstrated
for a diverse group of microorganisms such as Mycobacterium
tuberculosis and Leishmania donovani
(13). Specific mechanistic
models of how PTPs contribute to the development of infection and disease
progression by highly lethal organisms still remain unclear.Bacillus anthracis, a Gram-positive spore-forming bacterium, is
the etiologic agent of anthrax. The lethal toxin (LT) produced by B.
anthracis can cleave host cell mitogen-activated protein kinase kinases
(MAPKK), thereby affecting the immune response and the host ability to fight
the infection (15,
16). Macrophages are the
primary targets of anthrax LT. However, macrophages from only certain strains
of mice are susceptible to LT-mediated cell death
(17,
18). To date, there is no
known direct relation between MAPKK cleavage and LT-induced macrophage cell
death, as LT-resistant macrophages exhibit MAPKK cleavage
(19–21).
This suggests that another cellular target(s) may play a role in anthrax
pathogenesis.Previously, using a chemical genetic approach, we identified a class of
Cdc25 inhibitors that protected macrophages from cell death induced by anthrax
LT (22). Although Cdc25 was
not the cellular target, induction of anti-apoptotic responses by the
compounds via either the MAPK-dependent or -independent pathways was
responsible for the protective phenotype.In the present study we investigated if the previously identified
phosphatase inhibitors (22)
and their analogs produced any phenotypic changes in the B. anthracis
infection model. Two compounds that previously protected LT-treated
macrophages (22) also protect
B. anthracis-infected macrophages. Subsequent in vitro
phosphatase profiling studies identified CD45, a previously unknown target of
one of the small molecules, as the most sensitive enzyme to the inhibitor. We
then investigated the effect of CD45 reduction in anthrax pathogenesis both in
cells and in vivo by using antisense phosphorodiamidate morpholino
oligomers and mice engineered to express reduced levels of CD45. 相似文献