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Article ; Online: Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes.

Li, Weiguo / Sachidanandam, Kamakshi / Ergul, Adviye

2012 Volume 33, Issue 2, Page(s) 185–191

Abstract: Objectives: Cerebrovascular tone plays a key role in controlling cerebral blood flow. Our studies have demonstrated that the endothelin system is upregulated in type 2 diabetes leading to increased sensitivity to endothelin-1 and decreased relaxation in ...

Abstract	Objectives: Cerebrovascular tone plays a key role in controlling cerebral blood flow. Our studies have demonstrated that the endothelin system is upregulated in type 2 diabetes leading to increased sensitivity to endothelin-1 and decreased relaxation in basilar artery. While chronic endothelin A receptor blockade restored relaxation, selective endothelin B receptor blockade caused paradoxical constriction in diabetes. Whether this effect was due to activation of endothelin A receptors in the presence of endothelin B receptor blockade or due to the loss of vasculoprotective effects of endothelin B receptors remained unknown. The current study hypothesizes that due to the antagonism of the vasculoprotective endothelin receptor B, dual blockade will not be as effective as selective endothelin receptor A antagonism in improving cerebrovascular dysfunction in type 2 diabetes. Methods: These studies were done in non-obese, type 2 diabetic Goto-Kakizaki rats administered either vehicle, selective endothelin receptor A antagonist Atrasentan (5 mg/kg) or dual endothelin antagonist Bosentan (100 mg/kg) for 4 weeks. At termination, basilar arteries were collected and mounted on a wire myograph and cumulative dose-response curves to endothelin-1 (1-500 nM) and acetylcholine (1 nM-5 μm) were studied. Results: Basilar artery was highly sensitive to endothelin-1-mediated constriction in diabetic animals. While neither Atrasentan nor Bosentan affected endothelium-dependent vascular relaxation in control animals, both treatments improved the maximum dilatation in diabetes and Atrasentan also improved sensitivity to acetylcholine. Conclusion: In light of our previous data which showed that endothelin B receptors are vasculoprotective and blockade of this receptor worsens relaxation, current findings suggest that when blocked simultaneously with the endothelin receptor A, the endothelin receptor B antagonism is protective by reducing the hyperreactivity and improving cerebrovascular function in diabetes.
MeSH term(s)	Animals ; Atrasentan ; Bosentan ; Cerebral Arteries/drug effects ; Cerebral Arteries/metabolism ; Cerebral Arteries/physiopathology ; Cerebrovascular Circulation/drug effects ; Cerebrovascular Circulation/physiology ; Cerebrovascular Disorders/etiology ; Cerebrovascular Disorders/metabolism ; Cerebrovascular Disorders/physiopathology ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Diabetic Angiopathies/drug therapy ; Diabetic Angiopathies/metabolism ; Diabetic Angiopathies/physiopathology ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Male ; Pyrrolidines/pharmacology ; Rats ; Rats, Inbred Strains ; Receptor, Endothelin A/physiology ; Receptor, Endothelin B/physiology ; Sulfonamides/pharmacology ; Vasodilator Agents/pharmacology
Chemical Substances	Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Pyrrolidines ; Receptor, Endothelin A ; Receptor, Endothelin B ; Sulfonamides ; Vasodilator Agents ; Bosentan (Q326023R30) ; Atrasentan (V6D7VK2215)
Language	English
Publishing date	2012-05-11
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	424428-x
ISSN	1743-1328 ; 0161-6412
ISSN (online)	1743-1328
ISSN	0161-6412
DOI	10.1179/016164111X12881719352417
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Zs.A 1491: Show issues

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Article ; Online: Unexpected doxorubicin-mediated cardiotoxicity in sisters: possible role of polymorphisms in histamine n-methyl transferase.

Sachidanandam, Kamakshi / Gayle, Arlene A / Robins, H Ian / Kolesar, Jill M

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners

2012 Volume 19, Issue 3, Page(s) 269–272

Abstract: The anthracycline anticancer agent doxorubicin has long been recognized to induce a dose-limiting cardiotoxicity and may be associated with genes relevant to doxorubicin disposition. Recent reports suggest a role for a number of single nucleotide ... ...

Abstract	The anthracycline anticancer agent doxorubicin has long been recognized to induce a dose-limiting cardiotoxicity and may be associated with genes relevant to doxorubicin disposition. Recent reports suggest a role for a number of single nucleotide polymorphisms in anthracycline cardiotoxicity in children. We describe two adult sisters with anthracycline cardiotoxicity that developed after a relatively low dose of doxorubicin. One sister carried the variant genotype for histamine N-ethyl transferase (HNMT, rs17583889) while the other was heterozygous, suggesting a similar role for these genotypes in adults with anthracycline cardiotoxicity. Although this requires further study, these genotypes may be important in the clinical dosing, or use of the liposomal formulation of doxorubicin.
MeSH term(s)	Antibiotics, Antineoplastic/adverse effects ; Cardiotoxins/adverse effects ; Doxorubicin/adverse effects ; Female ; Genotype ; Heart Diseases/chemically induced ; Heart Diseases/enzymology ; Heart Diseases/genetics ; Histamine N-Methyltransferase/genetics ; Humans ; Polymorphism, Single Nucleotide ; Siblings
Chemical Substances	Antibiotics, Antineoplastic ; Cardiotoxins ; Doxorubicin (80168379AG) ; Histamine N-Methyltransferase (EC 2.1.1.8)
Language	English
Publishing date	2012-11-15
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1330764-2
ISSN	1477-092X ; 1078-1552
ISSN (online)	1477-092X
ISSN	1078-1552
DOI	10.1177/1078155212461022
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Zs.A 4488: Show issues

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Article: Oxidative stress and cardiovascular disease: antioxidants and unresolved issues.

Sachidanandam, Kamakshi / Fagan, Susan C / Ergul, Adviye

Cardiovascular drug reviews

2005 Volume 23, Issue 2, Page(s) 115–132

Abstract: Experimental and clinical studies suggest that oxidative stress contributes to the development and progression of cardiovascular disease. However, clinical trials with classic vitamin antioxidants failed to demonstrate any benefit in cardiovascular ... ...

Abstract	Experimental and clinical studies suggest that oxidative stress contributes to the development and progression of cardiovascular disease. However, clinical trials with classic vitamin antioxidants failed to demonstrate any benefit in cardiovascular outcomes. Recent advances in our understanding of mechanisms involved in free radical generation reinstate that a more comprehensive approach targeting the prevention of reactive oxygen species (ROS) formation early in the disease process may prove beneficial. Experimental studies and reviews in oxidative stress were selected to provide a better understanding of the roles of the reactive species in the initiation and progression of cardiovascular disease (CVD). Clinical studies that evaluated the efficacy of several classes of antioxidants in CVD were included in the second part of this review to discuss future therapeutic guidelines based on currently available evidence. In conclusion, before a potential role for antioxidants in the treatment of CVD is eliminated, more carefully designed studies with classic as well as new antioxidants in well-defined patient populations are warranted to provide a definitive answer.
MeSH term(s)	Animals ; Antioxidants/therapeutic use ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/etiology ; Clinical Trials as Topic ; Humans ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism
Chemical Substances	Antioxidants ; Reactive Oxygen Species
Language	English
Publishing date	2005-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	645099-4
ISSN	0897-5957
ISSN	0897-5957
DOI	10.1111/j.1527-3466.2005.tb00160.x
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Zs.A 2474: Show issues

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Article: Microvascular versus macrovascular dysfunction in type 2 diabetes: differences in contractile responses to endothelin-1.

Sachidanandam, Kamakshi / Harris, Alex / Hutchinson, Jimmie / Ergul, Adviye

Experimental biology and medicine (Maywood, N.J.)

2006 Volume 231, Issue 6, Page(s) 1016–1021

Abstract: Vascular dysfunction characterized by a hyperreactivity to vasoconstrictors and/or impaired vascular relaxation contributes to increased incidence of cardiovascular disease in diabetes. Endothelin (ET)-1, a potent vasoconstrictor, is chronically elevated ...

Abstract	Vascular dysfunction characterized by a hyperreactivity to vasoconstrictors and/or impaired vascular relaxation contributes to increased incidence of cardiovascular disease in diabetes. Endothelin (ET)-1, a potent vasoconstrictor, is chronically elevated in diabetes. However, the role of ET-1 in resistance versus larger vessel function in mild diabetes remains unknown. Accordingly, this study investigated vascular function of third-order mesenteric arteries and basilar arteries in control Wistar and Goto-Kakizaki (GK) rats, a model of mild Type 2 diabetes. Six weeks after the onset of diabetes, contractile responses to 0.1-100 nM ET-1 and relaxation responses to 1 nM-10 microM acetylcholine (ACh) in vessels preconstricted (baseline + 60%) with serotonin (5-HT) were assessed by myograph studies in the presence or absence of a nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine (L-NNA). Maximum contractile response to ET-1 was augmented in mesenteric vessels (155 +/- 18% in GK vs. 81 +/- 6% in control; n = 5-7) but not in the basilar artery (134 +/- 29% in GK vs. 107 +/- 17% in control; n = 4 per group). However, vascular relaxation was impaired in the basilar arteries (22 +/- 4% in GK vs. 53 +/- 7% in control; n = 4 per group) but not in mesenteric arteries of GK rats. Inhibition of NOS decreased the relaxation response of basilar arteries to 15 +/- 8% and 42 +/- 5% in GK and control rats, respectively; whereas, in resistance vessels, corresponding values were 56 +/- 7% and 89 +/- 3% (vs. 109 +/- 2% and 112 +/- 3% without NOS blockade), indicating the involvement of different vasorelaxation-promoting pathways in these vascular beds. These findings provide evidence that the ET system is activated even under mild hyperglycemia and that it contributes to the hyperreactivity of resistance vessels, therefore, the ET system may play an important role in elevated blood pressure in Type 2 diabetes.
MeSH term(s)	Acetylcholine/pharmacology ; Animals ; Basilar Artery/drug effects ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Endothelin-1/pharmacology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/physiopathology ; Enzyme Inhibitors/pharmacology ; Isometric Contraction/drug effects ; Male ; Mesenteric Arteries/drug effects ; Muscle Contraction/drug effects ; NG-Nitroarginine Methyl Ester/pharmacology ; Rats ; Rats, Inbred Strains ; Rats, Wistar ; Serotonin/pharmacology ; Vasoconstrictor Agents/pharmacology ; Vasodilator Agents/pharmacology
Chemical Substances	Endothelin-1 ; Enzyme Inhibitors ; Vasoconstrictor Agents ; Vasodilator Agents ; Serotonin (333DO1RDJY) ; Acetylcholine (N9YNS0M02X) ; NG-Nitroarginine Methyl Ester (V55S2QJN2X)
Language	English
Publishing date	2006-06
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1535-3702
ISSN	1535-3702
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Article ; Online: Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetes.

Sachidanandam, Kamakshi / Portik-Dobos, Vera / Kelly-Cobbs, Aisha I / Ergul, Adviye

Canadian journal of physiology and pharmacology

2010 Volume 88, Issue 6, Page(s) 616–621

Abstract: Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto-Kakizaki (GK) rats ...

Abstract	Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto-Kakizaki (GK) rats that selective ETA receptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases (MMP), whereas selective ETB receptor blockade augments this thickening. The goal of this study was to determine the effect of combined ETA and ETB receptor blockade on resistance vessel remodeling. Vessel structure, MMP activity, and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or bosentan (100 mg/kg per day) for 4 weeks (n = 7-9 per group). Bosentan completely prevented the increase in M/L ratio and MMP-2 activity in diabetes but paradoxically increased M/L ratio and MMP activation in control animals. Collagenase (MMP-13) activity and protein levels were significantly decreased in diabetes. Accordingly, collagen deposition was augmented in GK rats. Dual ET receptor antagonism improved enzyme activity and normalized MMP-13 levels in diabetic animals but blunted MMP-13 activity in control animals. In summary, current findings suggest that diabetes-mediated remodeling of resistance arteries is prevented by dual blockade of ETA and ETB receptors and that the relative role of ET receptors in the regulation of vascular structure differs in the control and disease states.
MeSH term(s)	Animals ; Blood Glucose/metabolism ; Body Weight/drug effects ; Bosentan ; Collagen Type I/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Endothelin Receptor Antagonists ; Male ; Matrix Metalloproteinase 13/metabolism ; Matrix Metalloproteinase 2/metabolism ; Mesenteric Arteries/drug effects ; Mesenteric Arteries/metabolism ; Mesenteric Arteries/pathology ; Rats ; Rats, Inbred Strains ; Rats, Wistar ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Tunica Media/drug effects ; Tunica Media/metabolism ; Tunica Media/pathology
Chemical Substances	Blood Glucose ; Collagen Type I ; Endothelin Receptor Antagonists ; Sulfonamides ; Matrix Metalloproteinase 13 (EC 3.4.24.-) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Bosentan (Q326023R30)
Language	English
Publishing date	2010-07-14
Publishing country	Canada
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/Y10-034
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Zs.A 589: Show issues

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Article ; Online: Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.

Argiris, Athanassios / Ghebremichael, Musie / Gilbert, Jill / Lee, Ju-Whei / Sachidanandam, Kamakshi / Kolesar, Jill M / Burtness, Barbara / Forastiere, Arlene A

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2013 Volume 31, Issue 11, Page(s) 1405–1414

Abstract: Purpose: We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN).: Patients and ... ...

Abstract	Purpose: We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. Results: Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. Conclusion: The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.
MeSH term(s)	Adult ; Age Factors ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Diarrhea/chemically induced ; Docetaxel ; Drug Administration Schedule ; ErbB Receptors/genetics ; Fatigue/chemically induced ; Female ; Gefitinib ; Genotype ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/genetics ; Head and Neck Neoplasms/pathology ; Humans ; Kaplan-Meier Estimate ; Leukopenia/chemically induced ; Male ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins p21(ras) ; Quinazolines/administration & dosage ; Quinazolines/adverse effects ; Taxoids/administration & dosage ; Taxoids/adverse effects ; Taxoids/therapeutic use ; Treatment Outcome ; ras Proteins
Chemical Substances	KRAS protein, human ; Proto-Oncogene Proteins ; Quinazolines ; Taxoids ; Docetaxel (15H5577CQD) ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2) ; Gefitinib (S65743JHBS)
Language	English
Publishing date	2013-03-04
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2012.45.4272
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 650: Show issues

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Article ; Online: Differential effects of diet-induced dyslipidemia and hyperglycemia on mesenteric resistance artery structure and function in type 2 diabetes.

Sachidanandam, Kamakshi / Hutchinson, Jim R / Elgebaly, Mostafa M / Mezzetti, Erin M / Wang, Mong-Heng / Ergul, Adviye

The Journal of pharmacology and experimental therapeutics

2009 Volume 328, Issue 1, Page(s) 123–130

Abstract: Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that ... ...

Abstract	Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that addition of a high-fat diet would exacerbate small artery remodeling, compliance, and vascular dysfunction in type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio, collagen abundance and turnover, and matrix metalloproteinase dynamics], mechanical properties (vessel stiffness), and reactivity to pressure and vasoactive factors were measured in third-order mesenteric arteries in control Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in diabetes. Addition of the high-fat diet altered collagen patterns (mature versus new collagen) in favor of matrix accumulation. Addition of a high-fat diet caused increased constriction to endothelin-1 (0.1-100 nM), showed impaired vasorelaxation to both acetylcholine (0.1 nM-1 microM) and sodium nitroprusside (0.1 nM-1 microM), and increased cardiovascular risk factors in diabetes. These results suggest that moderate elevations in blood glucose, as seen in our lean GK model of type 2 diabetes, promote resistance artery remodeling resulting in increased medial thickness, whereas addition of a high-fat diet contributes to diabetic vascular disease predominantly by impairing vascular reactivity in the time frame used for this study. Although differential in their vascular effects, both hyperglycemia and diet-induced dyslipidemia need to be targeted for effective prevention and treatment of diabetic vascular disease.
MeSH term(s)	Acetylcholine/pharmacology ; Angiography ; Animals ; Collagen/metabolism ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/physiopathology ; Diabetic Angiopathies/chemically induced ; Diabetic Angiopathies/physiopathology ; Diabetic Angiopathies/prevention & control ; Dietary Fats/adverse effects ; Disease Models, Animal ; Dyslipidemias/complications ; Dyslipidemias/physiopathology ; Humans ; Hyperglycemia/complications ; Hyperglycemia/physiopathology ; Male ; Matrix Metalloproteinases/metabolism ; Mesenteric Arteries/physiology ; Mesenteric Arteries/physiopathology ; Nitroprusside/pharmacology ; Rats ; Rats, Wistar ; Risk Factors ; Vascular Resistance/physiology ; Vasoconstriction ; Vasodilation/drug effects
Chemical Substances	Dietary Fats ; Nitroprusside (169D1260KM) ; Collagen (9007-34-5) ; Matrix Metalloproteinases (EC 3.4.24.-) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2009-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.108.142612
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Article ; Online: Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells.

Ikeda, Ryuji / Vermeulen, Lee C / Lau, Elim / Jiang, Zhisheng / Sachidanandam, Kamakshi / Yamada, Katsushi / Kolesar, Jill M

International journal of oncology

2011 Volume 38, Issue 2, Page(s) 513–519

Abstract: Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabine-resistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/ ... ...

Abstract	Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabine-resistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/GR cells were resistant to gemcitabine as well as paclitaxel and docetaxel but not carboplatin and irinotecan. The expression level of multidrug resistance protein 7 (MRP7) in A549/GR cells was higher than that in A549 cells, and the inhibitor of MRP7 by cepharanthine increased the sensitivity to gemcitabine in A549/GR cells. These findings indicate that cepharanthine reversed gemcitabine resistance. To determine predictive molecular markers of gemcitabine resistance for more effective treatment of these tumors, we performed PCR array. We identified that CDKN1A/p21, CYP3A5, microsomal epoxide hyrolase 1 (EPHX1) and ABCC6 (MRP6) were up-regulated >5-fold in A549/GR cells. Gemcitabine also induced the expression of p21 and CYP3A5 in A549 cells. A better understanding of the characterization and mechanism of the resistance to gemcitabine in A549/GR cells may help identify agents that reverse clinical gemcitabine resistance in NSCLC.
MeSH term(s)	Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/drug effects ; Biomarkers, Tumor/genetics ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; DNA, Neoplasm/genetics ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Drug Resistance, Neoplasm ; Gene Expression Profiling ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Antimetabolites, Antineoplastic ; Biomarkers, Tumor ; Cyclin-Dependent Kinase Inhibitor p21 ; DNA, Neoplasm ; RNA, Messenger ; Deoxycytidine (0W860991D6) ; gemcitabine (B76N6SBZ8R)
Language	English
Publishing date	2011-02
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1154403-x
ISSN	1791-2423 ; 1019-6439
ISSN (online)	1791-2423
ISSN	1019-6439
DOI	10.3892/ijo.2010.866
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Zs.A 3690: Show issues

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Article: Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes.

Harris, Alex K / Elgebaly, Mostafa M / Li, Weiguo / Sachidanandam, Kamakshi / Ergul, Adviye

American journal of physiology. Regulatory, integrative and comparative physiology

2008 Volume 294, Issue 4, Page(s) R1213–9

Abstract: Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic ... ...

Abstract	Diabetes increases the risk of stroke and contributes to poor clinical outcomes in this patient population. Myogenic tone of the cerebral vasculature, including basilar arteries, plays a key role in controlling cerebral blood flow. Increased myogenic tone is ameliorated with ET receptor antagonism in Type 1 diabetes. However, the role of endothelin-1 (ET-1) and its receptors in cerebrovascular dysfunction in Type 2 diabetes, a common comorbidity in stroke patients, remains poorly elucidated. Therefore, we hypothesized that 1) cerebrovascular dysfunction occurs in the Goto-Kakizaki (GK) model of Type 2 diabetes, and 2) pharmacological antagonism of ETA receptors ameliorates, while ETB receptor blockade augments vascular dysfunction. GK or control rats were treated with antagonists to either ETA (atrasentan, 5 mg.kg(-1).day(-1)) or ETB (A-192621, 15 or 30 mg.kg(-1).day(-1)) receptors for 4 wk and vascular function of basilar arteries was assessed using a wire myograph. GK rats exhibited increased sensitivity to ET-1. ET(A) receptor antagonism caused a rightward shift, indicating decreased sensitivity in diabetes, while it increased sensitivity to ET-1 in control rats. Endothelium-dependent relaxation was impaired in diabetes. ETA receptor blockade restored relaxation to control values in the GK animals with no significant effect in Wistar rats and ETB blockade with 30 mg.kg(-1).day(-1) A-192621 caused paradoxical constriction in diabetes. These studies demonstrate that cerebrovascular dysfunction occurs and may contribute to altered regulation of myogenic tone and cerebral blood flow in diabetes. While ETA receptors mediate vascular dysfunction, ETB receptors display differential effects. These results underscore the importance of ETA/ETB receptor balance and interactions in cerebrovascular dysfunction in diabetes.
MeSH term(s)	Acetylcholine/pharmacology ; Animals ; Atrasentan ; Basilar Artery/drug effects ; Basilar Artery/metabolism ; Basilar Artery/physiopathology ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Endothelin-1/metabolism ; Male ; Pyrrolidines/pharmacology ; Rats ; Rats, Wistar ; Receptor, Endothelin A/metabolism ; Receptor, Endothelin B/metabolism ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/pharmacology ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology ; Viper Venoms/pharmacology
Chemical Substances	A 192621 ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Endothelin-1 ; Pyrrolidines ; Receptor, Endothelin A ; Receptor, Endothelin B ; Vasoconstrictor Agents ; Vasodilator Agents ; Viper Venoms ; sarafotoxins s6 ; Acetylcholine (N9YNS0M02X) ; Atrasentan (V6D7VK2215)
Language	English
Publishing date	2008-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603839-6
ISSN	1522-1490 ; 0363-6119
ISSN (online)	1522-1490
ISSN	0363-6119
DOI	10.1152/ajpregu.00885.2007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Endothelial endothelin B receptor-mediated prevention of cerebrovascular remodeling is attenuated in diabetes because of up-regulation of smooth muscle endothelin receptors.

Kelly-Cobbs, Aisha I / Harris, Alex K / Elgebaly, Mostafa M / Li, Weiguo / Sachidanandam, Kamakshi / Portik-Dobos, Vera / Johnson, Maribeth / Ergul, Adviye

The Journal of pharmacology and experimental therapeutics

2010 Volume 337, Issue 1, Page(s) 9–15

Abstract: Structure and function of the cerebrovasculature is critical for ischemic stroke outcome. We showed that diabetes causes cerebrovascular remodeling by activation of the endothelin A (ET(A)) receptors. The goal of this study was to test the hypotheses ... ...

Abstract	Structure and function of the cerebrovasculature is critical for ischemic stroke outcome. We showed that diabetes causes cerebrovascular remodeling by activation of the endothelin A (ET(A)) receptors. The goal of this study was to test the hypotheses that vasculoprotective endothelial ET(B) receptors are decreased and pharmacological inhibition of the ET(B) receptor augments vascular remodeling of middle cerebral arteries (MCAs) in type 2 diabetes. MCA structure, matrix metalloprotease (MMP) activity, and matrix proteins as well as ET(A) and ET(B) receptor profiles were assessed in control Wistar and diabetic Goto-Kakizaki rats treated with vehicle, the ET(B) receptor antagonist (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-[(2,6-diethylphenyl)amino]-2-oxoethyl]-2-(4-propoxyphenyl)pyrrolidine-3-carboxylic acid (A192621) (30 mg/kg/day), or the dual ET receptor antagonist bosentan (100 mg/kg/day) for 4 weeks. Diabetes increased vascular smooth muscle (VSM) ET(A) and ET(B) receptors; the increase was prevented by chronic bosentan treatment. MCA wall thickness was increased in diabetes, and this was associated with increased MMP-2 activity and collagen deposition but reduced MMP-13 activity. Because of up-regulation of VSM ET receptors in diabetes, selective ET(B) receptor antagonism with A192621 blunts this response, and combined ET(A) and ET(B) receptor blockade with bosentan completely prevents this response. On the other hand, A192621 treatment augmented remodeling in control animals, indicating a physiological protective role for this receptor subtype. Attenuation of changes in ET receptor profile with bosentan treatment suggests that ET-1 has a positive feedback on the expression of its receptors in the cerebrovasculature. These results emphasize that ET receptor antagonism may yield different results in healthy and diseased states.
MeSH term(s)	Animals ; Cerebrovascular Circulation/physiology ; Diabetes Mellitus, Type 2/metabolism ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelin B Receptor Antagonists ; Endothelin Receptor Antagonists ; Male ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Pyrrolidines/pharmacology ; Rats ; Rats, Wistar ; Receptor, Endothelin B/physiology ; Receptors, Endothelin/biosynthesis ; Receptors, Endothelin/physiology ; Up-Regulation/drug effects ; Up-Regulation/physiology
Chemical Substances	A 192621 ; Endothelin B Receptor Antagonists ; Endothelin Receptor Antagonists ; Pyrrolidines ; Receptor, Endothelin B ; Receptors, Endothelin
Language	English
Publishing date	2010-12-23
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.110.175380
Database	MEDical Literature Analysis and Retrieval System OnLINE

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