A Novel Sesquiterpene Lactone Xanthatin-13-(pyrrolidine-2-carboxylic acid) Isolated from Burdock Leaf Up-Regulates Cells’ Oxidative Stress Defense Pathway

The aim of our study was to identify novel molecules able to induce an adaptative response against oxidative stress during the first stages of metabolic syndrome. A cellular survival in vitro test against H2O2-based test was applied after pretreatment with various natural bitter Asteraceae extracts. This screening revealed potent protection from burdock leaf extract. Using chromatography and LC-MS—RMN, we then isolated and identified an original sesquiterpene lactone bioactive molecule: the Xanthatin-13-(pyrrolidine-2-carboxylic acid) (XPc). A real-time RT-qPCR experiment was carried out on three essential genes involved in oxidative stress protection: GPx, SOD, and G6PD. In presence of XPc, an over-expression of the G6PD gene was recorded, whereas no modification of the two others genes could be observed. A biochemical docking approach demonstrated that XPc had a high probability to directly interact with G6PD at different positions. One of the most probable docking sites corresponds precisely to the binding site of AG1, known to stabilize the G6PD dimeric form and enhance its activity. In conclusion, this novel sesquiterpene lactone XPc might be a promising prophylactic bioactive agent against oxidative stress and inflammation in chronic diseases such as metabolic syndrome or type 2 diabetes.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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Characterization of Apoptosis, Autophagy and Oxidative Stress in Pancreatic Islets Cells and Intestinal Epithelial Cells Isolated from Equine Metabolic Syndrome (EMS) Horses

International Journal of Molecular Sciences ◽

10.3390/ijms19103068 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3068

Author(s):

Katarzyna Kornicka ◽

Agnieszka Śmieszek ◽

Jolanta Szłapka-Kosarzewska ◽

Jennifer Irwin Houston ◽

Michael Roecken ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Pancreatic Islets ◽

Building Blocks ◽

Protective Mechanism ◽

Endocrine Disorders ◽

Intestinal Epithelial ◽

Epithelial Stem Cells ◽

Equine Metabolic Syndrome

Endocrine disorders are becoming an increasing problem in both human and veterinary medicine. In recent years, more and more horses worldwide have been suffering from equine metabolic syndrome (EMS). This metabolic disorder is characterized by pathological obesity, hyperinsulinaemia, hyperglycaemia and insulin resistance. Although metabolic disorders, including diabetes, have been extensively studied, there are still no data on the molecular effects of EMS in horses. Thus, the aim of this study was to evaluate apoptosis, oxidative stress, autophagy and microRNA (miR) expression in multipotent intestinal epithelial stem cells (IECs) and pancreatic islets (PIs) isolated post mortem form healthy and EMS diagnosed horses. Our group was the first to describe how EMS affects IEC and PI aging and senescence. First, we evaluated isolation and culture protocol for these cells and subsequently established their metabolic status in vitro. Both IECs and PIs isolated from EMS horses were characterized by increased apoptosis and senescence. Moreover, they accumulated elevated levels of reactive oxygen species (ROS). Here we have observed that autophagy/mitophagy may be a protective mechanism which allows those cells to maintain their physiological function, clear protein aggregates and remove damaged organelles. Furthermore, it may play a crucial role in reducing endoplasmic reticulum (ER) stress. This protective mechanism may help to overcome the harmful effects of ROS and provide building blocks for protein and ATP synthesis.

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The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

Endocrinology ◽

10.1210/en.2013-2143 ◽

2014 ◽

Vol 155 (8) ◽

pp. 2810-2819 ◽

Cited By ~ 20

Author(s):

Taichi Sugizaki ◽

Mitsuhiro Watanabe ◽

Yasushi Horai ◽

Nao Kaneko-Iwasaki ◽

Eri Arita ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Insulin Signaling ◽

Metabolic Diseases ◽

In Vitro Study ◽

Liver X Receptor ◽

Gene Expressions ◽

The Metabolic Syndrome ◽

Increased Risk

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

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Synthesis and anticancer activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides against PC-3 prostate cancer cells

Pharmacology and Drug Toxicology ◽

10.33250/vol13iss5pp331-337 ◽

2019 ◽

Vol 13 (5) ◽

pp. 331-337

Author(s):

S. A. Demchenko ◽

Yu. A. Fedchenkova ◽

T. А. Bukhtiarova ◽

L. S. Bobkova ◽

V. V. Sukhoveev ◽

...

Keyword(s):

Prostate Cancer ◽

Carboxylic Acid ◽

Antitumor Activity ◽

Cancer Cells ◽

Quaternary Salt ◽

In Vitro Test ◽

Prostate Cancer Cells ◽

Naoh Solution ◽

Acid Arylamides

Pharmacotherapy of prostate cancer is an important part in combating oncologic diseases. This is very relevant, because prostate cancer is a cause of 10 % of deaths from all cancerous diseases in males. The aim of the study – to synthesize novel derivatives of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides and to evaluate their antitumor activity against PC-3 prostate cancer cells. By reaction of equimolar amounts of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with a-amino-4-chloroacetophenone chlorohydrate, 3-(4-chlorophenyl)-6,7,8,9- tetrahydro-5Н-imidazo[1,2-a]azepine was synthesized. By alkylation of a-bromo-4-іsopropylacetophenone in ethylacetate and following treatment of the obtained intermediary quaternary salt with excess of 5 % NaOH solution,1-(41-isopropylphenyl)-4-(42chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene was synthesized. By boiling it with equimolar amounts of correspondding arylisocyanates in dried benzol, an array of 1-(41-iso propylphenyl)-4(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid arylamides were synthesized. Structure and purity of all compounds obtained were confirmed by data of MR1Н spectroscopy. Lipophilicity (LogP) of compounds 6 and 8 a-i was calculated with the ACD LogP program. Antitumor activity of 1-(41-isopropylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd]azulene-2-carboxylic acid (3-methylphenyl) and (3-methoxyphenyl)-amides was evaluated at in vitro test on prostate cancer PC-3 cell lines. It is indicated, that at concentration of 10–5 M these compounds exceed 5-fluorouracil as comparison drug in inhibiting PC-3 prostate cancer cells growth by 52.32 % and 3.93 % correspondingly. The data obtained substantiate feasibility of further studies of 1-(41-isopro pylphenyl)-4-(42-chlorophenyl)-5,6,7,8-tetrahydro-2,4а-diazacyclopenta[cd] azulene-2-carboxylic acid arylamides as new, potential antitumor medicines for prostate cancer treatment.

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Chromosomal Instability in Cultured Mouse Hematopoietic Cells Associated with Oxidative Stress

Blood ◽

10.1182/blood.v118.21.4819.4819 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4819-4819

Author(s):

Alice M. Liu ◽

William W. Qu ◽

Xia Liu

Keyword(s):

Oxidative Stress ◽

Bone Marrow ◽

Genomic Instability ◽

Chromosomal Instability ◽

Conflicts Of Interest ◽

Hematopoietic Cells ◽

Genetic Alterations ◽

In Vitro Test ◽

Hematopoietic Stem

Abstract Abstract 4819 Hematopoietic stem cells (HSCs) that give rise to all blood cell types are important vehicles for cell-based and gene therapies. After isolation from the bone marrow, HSCs are often cultured in laboratory settings for purposes of ex vivo expansion, gene transduction, and bone marrow transplantation for the treatment of various disorders of the blood and immune systems. While undergoing proliferation and differentiation in vitro, test tube and dish culturing can potentially induce genomic instability in HSCs due to prolonged culturing periods or the exposure to increased levels of oxygen. Here we demonstrate that in vitro culturing outside their bone marrow niches, HSCs may change even under very short durations of time. Lineage− Scal-1+ c-Kit+ (LSK) cells that are enriched with HSCs revealed significant levels of genomic instability in culture, as evidenced by the emergence of aneuploidy cells. To further determine the effects of in vitro culturing conditions, whole bone marrow cells were cultured in a hypoxic environment of 2–3% oxygen, mimicking conditions inside the body's bone marrow. In this case, cells proved to undergo less genetic alterations. Proper dosages of the antioxidant N-Acetyl-Cysteine (NAC) similarly decreased occurrences of chromosomal changes. Furthermore, in vitro normoxic culture-induced chromosomal instability was enhanced in aged hematopoietic cells compared to that in young hematopoietic cells due to noted increased oxidative stress in aged cells. These results reveal that in vitro cell culturing does indeed cause genomic instability in hematopoietic cells. Reduced oxygen levels and additions of antioxidants can be employed as a possible agent to lower oxidative stress and decrease chances of transformation. Additionally, since hematopoietic cells are commonly developed in laboratory settings before transplantation for patient treatment, our findings raise a concern for using cultured hematopoietic cells for therapeutic purposes. Note: Alice Liu and William Qu contributed equally to this work. Disclosures: No relevant conflicts of interest to declare.

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Petrobactin Protects against Oxidative Stress and Enhances Sporulation Efficiency inBacillus anthracisSterne

mBio ◽

10.1128/mbio.02079-18 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 5

Author(s):

Ada K. Hagan ◽

Yael M. Plotnick ◽

Ryan E. Dingle ◽

Zachary I. Mendel ◽

Stephen R. Cendrowski ◽

...

Keyword(s):

Oxidative Stress ◽

Bacillus Anthracis ◽

Iron Acquisition ◽

Sporulation Medium ◽

Term Survival ◽

Content Type ◽

Stress Protection ◽

Dormant Spore ◽

Iron Iron

ABSTRACTBacillus anthracisis a Gram-positive bacillus that under conditions of environmental stress, such as low nutrients, can convert from a vegetative bacillus to a highly durable spore that enables long-term survival. The sporulation process is regulated by a sequential cascade of dedicated transcription factors but requires key nutrients to complete, one of which is iron. Iron acquisition by the iron-scavenging siderophore petrobactin is required for vegetative growth ofB. anthracisunder iron-depleted conditions and in the host. However, the extent to which petrobactin is involved in spore formation is unknown. This work shows that efficientin vitrosporulation ofB. anthracisrequires petrobactin, that the petrobactin biosynthesis operon (asbAto-F) is induced prior to sporulation, and that the siderophore itself associates with spores. Petrobactin is also required for oxidative stress protection during late-stage growth and for wild-type levels of sporulation in sporulation medium. Sporulation in bovine blood was found to be petrobactin dependent. Collectively, thein vitrocontributions of petrobactin to sporulation as well as growth imply that petrobactin may be required forB. anthracistransmission via the spore during natural infections, in addition to its key known functions during active anthrax infections.IMPORTANCEBacillus anthraciscauses the disease anthrax, which is transmitted via its dormant, spore phase. However, conversion from bacillus to spore is a complex, energetically costly process that requires many nutrients, including iron.B. anthracisrequires the siderophore petrobactin to scavenge iron from host environments. We show that, in the Sterne strain, petrobactin is required for efficient sporulation, even when ample iron is available. The petrobactin biosynthesis operon is expressed during sporulation, and petrobactin is biosynthesized during growth in high-iron sporulation medium, but instead of being exported, the petrobactin remains intracellular to protect against oxidative stress and improve sporulation. It is also required for full growth and sporulation in blood (bovine), an essential step for anthrax transmission between mammalian hosts.

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Comparison of enzymically glucuronidated flavonoids with flavonoid aglycones in an in vitro cellular model of oxidative stress protection

In Vitro Cellular & Developmental Biology - Animal ◽

10.1007/s11626-007-9072-y ◽

2008 ◽

Vol 44 (3-4) ◽

pp. 73-80 ◽

Cited By ~ 9

Author(s):

David E. Stevenson ◽

Janine M. Cooney ◽

Dwayne J. Jensen ◽

Reginald Wibisono ◽

Aselle Adaim ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Model ◽

Flavonoid Aglycones ◽

Stress Protection ◽

Oxidative Stress Protection

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The synthesis and the antioxidant activity of 1-phenoxymethyl-4-aryl-5,6,7,8-tetrahydro-2a,4a,8a-triazacyclopenta[cd]azulene-3-carboxylic (or carbothionic) acid derivatives

Pharmacia ◽

10.3897/pharmacia.68.e60195 ◽

2021 ◽

Vol 68 (1) ◽

pp. 251-258

Author(s):

Sergii Demchenko ◽

Hanna Yeromina ◽

Yulia Fedchenkova ◽

Zinaida Ieromina ◽

Vitaliy Yaremenko ◽

...

Keyword(s):

Oxidative Stress ◽

Antioxidant Activity ◽

Ascorbic Acid ◽

Carboxylic Acid ◽

In Silico ◽

Pharmacokinetic Profile ◽

High Antioxidant Activity ◽

Pharmacological Screening

New 1-phenoxymethyl-4-aryl-5,6,7,8-tetrahydro-2а,4a,8a-triazacyclopenta[cd]azulene-3-carboxylic (or carbothionic) acid derivatives have been designed, synthesized and evaluated for their in vitro antioxidant activity under conditions of the artificial oxidative stress using ionol, ascorbic acid and α-tocopherol as the reference drugs. It has been found that 1-phenoxymethyl-4-aryl-5,6,7,8-tetrahydro-2а,4a,8a-triazacyclopenta[cd]azulene-3-carbothionic acid derivatives 9b, 9c, 9d, 9e, 9f, 9i and 1-phenoxymethyl-4-(41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8-triazacyclopenta[cd]azulene-3-carboxylic acid phenylamide 10 reveal a high antioxidant activity and a good in silico pharmacokinetic profile. The data obtained allowed us to select the most promising objects from the substances synthesized for further pharmacological screening for the presence of the antioxidant activity in vivo.

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Effect of a short-term diet and exercise intervention on oxidative stress, inflammation, MMP-9, and monocyte chemotactic activity in men with metabolic syndrome factors

Journal of Applied Physiology ◽

10.1152/japplphysiol.01292.2005 ◽

2006 ◽

Vol 100 (5) ◽

pp. 1657-1665 ◽

Cited By ~ 141

Author(s):

Christian K. Roberts ◽

Dean Won ◽

Sandeep Pruthi ◽

Silvia Kurtovic ◽

Ram K. Sindhu ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Lifestyle Modification ◽

Fluorometric Detection ◽

Reactive Protein ◽

Inflammatory Protein ◽

Chemotactic Protein ◽

Metalloproteinase 9 ◽

Macrophage Inflammatory Protein

The present study was designed to examine the effects of lifestyle modification on key contributing factors to atherogenesis, including oxidative stress, inflammation, chemotaxis, and cell adhesion. Obese men ( n = 31), 15 of whom had metabolic syndrome, were placed on a high-fiber, low-fat diet in a 3-wk residential program where food was provided ad libitum and daily aerobic exercise was performed. In each subject, pre- and postintervention fasting blood was drawn for circulating levels of serum lipids, glucose and insulin (for estimation of insulin sensitivity), oxidative stress-generating enzyme myeloperoxidase and marker 8-isoprostaglandin F2α, the inflammatory protein C-reactive protein, soluble ICAM-1 as an indicator of endothelial activation, sP-selectin as a marker of platelet activation, the chemokine macrophage inflammatory protein-1α, and total matrix metalloproteinase-9. Using subject sera and human aortic endothelial cell culture systems, we measured VCAM-1 cell surface abundance and monocyte chemotactic protein-1, nitric oxide, superoxide, and hydrogen peroxide production in vitro by fluorometric detection. Also determined in vitro was serum-induced, monocyte adhesion and monocyte chemotactic activity. After 3 wk, significant reductions ( P < 0.05) in body mass index, all serum lipids and lipid ratios, fasting glucose, insulin, homeostasis model assessment for insulin resistance, myeloperoxidase, 8-isoprostaglandin F2α, C-reactive protein, soluble ICAM-1, soluble P-selectin, macrophage inflammatory protein-1α, and matrix metalloproteinase-9 were noted. In vitro, serum-stimulated cellular VCAM-1 expression, monocyte chemotactic protein-1 production, and fluorometric detection of superoxide and hydrogen peroxide production decreased, whereas a concomitant increase in NO production was noted (all P < 0.01). Additionally, both monocyte adhesion ( P < 0.05) and MCA ( P < 0.01) decreased. Nine of 15 were no longer positive for metabolic syndrome postintervention. Intensive lifestyle modification may ameliorate novel coronary artery disease risk factors in men with metabolic syndrome factors before reversal of obesity.

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