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Article: Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats.

Palfrey, Henry A / Kumar, Avinash / Pathak, Rashmi / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Research square

2024

Abstract: Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and ... ...

Abstract	Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. Thus, Methods: Six-week-old adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with vehicle (water) or Results: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. Conclusion: Adverse cardiac outcomes in HChol were enhanced with sitagliptin administration and such effects were alleviated by Met. Our findings could be significant for understanding the risk-benefit of sitagliptin in type 2 diabetics who are known to consume atherogenic diets.
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-4075353/v1
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Article ; Online: Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet.

Pathak, Rashmi / Kumar, Avinash / Palfrey, Henry A / Stone, Kirsten P / Raju, Narayan R / Gettys, Thomas W / Murthy, Subramanyam N

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2022 Volume 71, Issue 5-6, Page(s) 711–722

Abstract: Objective: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, ...

Abstract	Objective: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. Methods: Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. Results: Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1β) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. Conclusions: The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.
MeSH term(s)	Animals ; Cholesterol, Dietary ; Diabetes Mellitus, Type 2/drug therapy ; Diet ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Fibrosis ; Hypercholesterolemia ; Hypoglycemic Agents ; Inflammation/pathology ; Male ; Necrosis/drug therapy ; Prospective Studies ; Rats ; Rats, Sprague-Dawley ; Sitagliptin Phosphate/pharmacology ; Sitagliptin Phosphate/therapeutic use
Chemical Substances	Cholesterol, Dietary ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2022-05-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-022-01572-4
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Article: High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

Kumar, Avinash / Pathak, Rashmi / Palfrey, Henry A / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Nutrition & metabolism

2020 Volume 17, Page(s) 2

Abstract: Background: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. ... ...

Abstract	Background: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. Methods: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. Results: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. Conclusion: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.
Language	English
Publishing date	2020-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2160376-5
ISSN	1743-7075
ISSN	1743-7075
DOI	10.1186/s12986-019-0422-z
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Article: High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats

Kumar, Avinash / Pathak, Rashmi / Palfrey, Henry A / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Nutrition & metabolism. 2020 Dec., v. 17, no. 1

2020

Abstract: BACKGROUND: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. ... ...

Abstract	BACKGROUND: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. METHODS: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. RESULTS: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. CONCLUSION: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.
Keywords	Western diets ; ad libitum feeding ; cholesterol ; collagen ; fatty liver ; fibrosis ; hepatotoxicity ; homocysteine ; hypercholesterolemia ; hypoglycemic agents ; immunohistochemistry ; laboratory animals ; liver ; males ; methionine ; oxidative stress ; rats ; risk factors ; staining
Language	English
Dates of publication	2020-12
Size	p. 2.
Publishing place	BioMed Central
Document type	Article
ISSN	1743-7075
DOI	10.1186/s12986-019-0422-z
Database	NAL-Catalogue (AGRICOLA)

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Article: The metabolism and significance of homocysteine in nutrition and health.

Kumar, Avinash / Palfrey, Henry A / Pathak, Rashmi / Kadowitz, Philip J / Gettys, Thomas W / Murthy, Subramanyam N

Nutrition & metabolism

2017 Volume 14, Page(s) 78

Abstract: An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age- ...

Abstract	An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B
Language	English
Publishing date	2017-12-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2160376-5
ISSN	1743-7075
ISSN	1743-7075
DOI	10.1186/s12986-017-0233-z
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Article ; Online: The incretin enhancer, sitagliptin, exacerbates expression of hepatic inflammatory markers in rats fed a high-cholesterol diet.

Pathak, Rashmi / Kumar, Avinash / Palfrey, Henry A / Forney, Laura A / Stone, Kirsten P / Raju, Narayan R / Gettys, Thomas W / Murthy, Subramanyam N

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2019 Volume 68, Issue 7, Page(s) 581–595

Abstract: Objective: Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin ... ...

Abstract	Objective: Hypercholesterolemia is associated with the development of a pro-inflammatory state and is a documented risk factor for progression to insulin resistance, nonalcoholic fatty liver and cardiovascular diseases. Sitagliptin is an incretin enhancer that improves glucose tolerance by inhibiting dipeptidyl peptidase-4, but it also has reported anti-inflammatory effects. The current study was thus undertaken to examine the interactions of dietary Cholesterol (Cho) and sitagliptin on markers of inflammation. Methods: Male Sprague-Dawley rats were provided diets high in Cho and gavaged with vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day) from day 10 through day 35. Molecular methods were used to analyze the lipid profile and inflammatory markers in liver and serum samples. H&E-stained liver sections were used for histopathological evaluation. Hepatic influx of mononuclear cells and necrosis were assessed by immunohistochemistry. Results: Sitagliptin reduced triglyceride and Cho levels in serum of rats on the control diet but these effects were abrogated in rats on the high-Cho diet. Sitagliptin produced a significant increase in the expression of hepatic inflammatory markers (Tnfa, Il1b, and Mcp1) and a corresponding increase in serum TNFα and IL-1β in rats on the high-Cho diet, but it had no effect on rats on the control diet. Additionally, sitagliptin had no effect on liver morphology in rats on the control diet, but it produced hepatic histopathological changes indicative of necrosis and mononuclear cell infiltration in rats on the high-Cho diet. These mononuclear cells were identified as macrophages and T cells. Conclusion: When provided in the context of a high-Cho diet, these findings reveal previously unrecognized hepato-inflammatory effects of sitagliptin that are accompanied by evidence of hepatic necrosis and mononuclear cell infiltration.
MeSH term(s)	Animals ; Cholesterol, Dietary/pharmacology ; Cytokines/metabolism ; Hypercholesterolemia/metabolism ; Hypercholesterolemia/pathology ; Incretins/pharmacology ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Male ; Rats, Sprague-Dawley ; Sitagliptin Phosphate/pharmacology
Chemical Substances	Cholesterol, Dietary ; Cytokines ; Incretins ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2019-05-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-019-01243-x
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Article ; Online: New approaches to the treatment of pulmonary hypertension: from bench to bedside.

Murthy, Subramanyam N / Nossaman, Bobby D / Kadowitz, Philip J

Cardiology in review

2010 Volume 18, Issue 2, Page(s) 76–84

Abstract: Pulmonary hypertension (PH) is a severe, life-threatening disease for which there are no effective curative therapies. A diverse group of agents such as prostacyclins, endothelin antagonists, phosphodiesterase inhibitors, calcium channel blockers, ... ...

Abstract	Pulmonary hypertension (PH) is a severe, life-threatening disease for which there are no effective curative therapies. A diverse group of agents such as prostacyclins, endothelin antagonists, phosphodiesterase inhibitors, calcium channel blockers, diuretics, inotropic agents, and anticoagulants are used to treat PH; however, none of these agents have a marked effect upon survival. Among the new agents that promise treatment of PH are rho-kinase inhibitors and soluble guanylate cyclase stimulators. Although these new classes of agents have beneficial effects in experimental animal models and clinical studies, they are not selective in their actions on the pulmonary vascular bed. This manuscript reviews the actions of rho-kinase inhibitors and soluble guanylate cyclase stimulators on the pulmonary vascular bed. It is our hypothesis that these new agents may be more effective than current therapies in the treatment of PH. Moreover, new methods in the delivery of these agents to the lung need to be developed so that their main effects will be exerted in the pulmonary vascular bed and their systemic effects can be minimized or avoided.
MeSH term(s)	Amides/pharmacology ; Amides/therapeutic use ; Animals ; Calcium Channel Blockers/therapeutic use ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Evidence-Based Medicine ; Guanylate Cyclase/therapeutic use ; Humans ; Hypertension, Pulmonary/drug therapy ; Hypertension, Pulmonary/mortality ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Muscle Contraction/drug effects ; Muscle Contraction/physiology ; Muscle, Smooth/drug effects ; Muscle, Smooth/physiology ; Oxadiazoles/pharmacology ; Oxadiazoles/therapeutic use ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Receptors, Cytoplasmic and Nuclear/therapeutic use ; Soluble Guanylyl Cyclase ; Vasodilator Agents/therapeutic use ; rho-Associated Kinases/antagonists & inhibitors
Chemical Substances	4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine ; Amides ; Calcium Channel Blockers ; Enzyme Inhibitors ; Imidazoles ; Oxadiazoles ; Pyridines ; Receptors, Cytoplasmic and Nuclear ; Vasodilator Agents ; Y 27632 (138381-45-0) ; rho-Associated Kinases (EC 2.7.11.1) ; Guanylate Cyclase (EC 4.6.1.2) ; Soluble Guanylyl Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2010-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1294965-6
ISSN	1538-4683 ; 1061-5377
ISSN (online)	1538-4683
ISSN	1061-5377
DOI	10.1097/CRD.0b013e3181cbcbf3
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Zs.A 4491: Show issues

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Article ; Online: Role of the RhoA/Rho-kinase pathway in the regulation of pulmonary vasoconstrictor function.

Nossaman, Bobby D / Nossaman, Vaughn E / Murthy, Subramanyam N / Kadowitz, Philip J

Canadian journal of physiology and pharmacology

2010 Volume 88, Issue 1, Page(s) 1–8

Abstract: Calcium is the major intracellular messenger that triggers smooth muscle contraction. The study of calcium-binding proteins, such as calmodulin and its downstream effectors, reveals critical regulation of smooth muscle contraction by protein kinases and ... ...

Abstract	Calcium is the major intracellular messenger that triggers smooth muscle contraction. The study of calcium-binding proteins, such as calmodulin and its downstream effectors, reveals critical regulation of smooth muscle contraction by protein kinases and phosphatases. Moreover, the small GTP-binding protein RhoA and its downstream effector protein, Rho-kinase, have been shown to play a novel role in the regulation of smooth muscle contraction. Studies have shown that the activation of Rho-kinase is involved in the development of endothelial dysfunction, inflammation, restenosis, and increased vascular tone in a number of cardiovascular disorders. Because inhibitors of this pathway promote vasodilation independent of the mechanism that increases vasoconstrictor tone, it is our hypothesis that Rho-kinase is constitutively active in regulating vasoconstrictor tone in the pulmonary and systemic vascular beds. Studies in the literature suggest that the RhoA/Rho-kinase pathway has an important role in the pathogenesis of pulmonary hypertension.
MeSH term(s)	Animals ; Humans ; Pulmonary Artery/enzymology ; Pulmonary Veins/enzymology ; Signal Transduction/physiology ; Vasoconstriction/physiology ; rho-Associated Kinases/physiology ; rhoA GTP-Binding Protein/physiology
Chemical Substances	rho-Associated Kinases (EC 2.7.11.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2010-01
Publishing country	Canada
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/Y09-092
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Article: Cytotoxic effects of oxysterols produced during ozonolysis of cholesterol in murine GT1-7 hypothalamic neurons.

Sathishkumar, K / Murthy, Subramanyam N / Uppu, Rao M

Free radical research

2007 Volume 41, Issue 1, Page(s) 82–88

Abstract: ... both ChSeco and ChEpo resulted in the generation of ROS, the magnitude of which was comparable. N-acetyl-l ...

Abstract	Ozone present in the photochemical smog or generated at the inflammatory sites is known to oxidize cholesterol and its 3-acyl esters. The oxidation results in the formation of multiple "ozone-specific" oxysterols, some of which are known to cause abnormalities in the metabolism of cholesterol and exert cytotoxicity. The ozone-specific oxysterols have been shown to favor the formation of atherosclerotic plaques and amyloid fibrils involving pro-oxidant processes. In the present communication, cultured murine GT1-7 hypothalamic neurons were studied in the context of cholesterol metabolism, formation of reactive oxygen species, intracellular Ca2 + levels and cytotoxicity using two most commonly occurring cholesterol ozonolysis products, 3beta- hydroxy-5-oxo-5,6-secocholestan-6-al (ChSeco) and 5beta, 6beta-epoxy-cholesterol (ChEpo). It was found that ChSeco elicited cytotoxicity at lower concentration (IC50 = 21 +/- 2.4 microM) than did ChEpo (IC50 = 43 +/- 3.7 microM). When tested at their IC50 concentrations in GT1-7 cells, both ChSeco and ChEpo resulted in the generation of ROS, the magnitude of which was comparable. N-acetyl-l-cysteine and Trolox attenuated the cytotoxic effects of ChSeco and ChEpo. The intracellular Ca2 + levels were not altered by either ChSeco or ChEpo. Methyl-beta-cyclodextrins, which cause depletion of cellular cholesterol, prevented ChSeco- but not ChEpo-induced cytotoxicity. The cell death caused by ChEpo, but not ChSeco, was prevented by exogenous cholesterol. Although oxidative stress plays a significant role, the results of the present study indicate differences in the pathways of cell death induced by ChSeco and ChEpo in murine GT1-7 hypothalamic neurons.
MeSH term(s)	Animals ; Calcium/metabolism ; Cells, Cultured ; Cholesterol/metabolism ; Mice ; Neurons/metabolism ; Ozone/metabolism ; Reactive Oxygen Species/metabolism ; beta-Cyclodextrins/metabolism
Chemical Substances	Reactive Oxygen Species ; beta-Cyclodextrins ; methyl-beta-cyclodextrin ; Ozone (66H7ZZK23N) ; Cholesterol (97C5T2UQ7J) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2007-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1194130-3
ISSN	1029-2470 ; 1071-5762
ISSN (online)	1029-2470
ISSN	1071-5762
DOI	10.1080/10715760600950566
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Article: Therapeutic effects of Nigella sativa on chronic HAART-induced hyperinsulinemia in rats.

Chandra, Surabhi / Murthy, Subramanyam N / Mondal, Debasis / Agrawal, Krishna C

Canadian journal of physiology and pharmacology

2009 Volume 87, Issue 4, Page(s) 300–309

Abstract: Prolonged use of highly active antiretroviral therapy (HAART) is associated with insulin resistance in HIV-1-positive patients. Small animal models that recapitulate the long-term effects of HAART may facilitate the identification of therapeutic agents ... ...

Abstract	Prolonged use of highly active antiretroviral therapy (HAART) is associated with insulin resistance in HIV-1-positive patients. Small animal models that recapitulate the long-term effects of HAART may facilitate the identification of therapeutic agents to suppress these side effects. We investigated the protective effects of black seed oil (BSO) from Nigella sativa in Sprague-Dawley rats treated with a daily HAART regimen for 7 months. The antiretroviral drugs, consisting of nelfinavir (200 mg/kg), zidovudine (50 mg/kg), and efavirenz (20 mg/kg), were mixed with diet with or without BSO (400 microL/kg) supplementation. Significant increases in insulin and C-peptide levels were observed in HAART-treated groups, and concomitant BSO treatment reduced this hyperinsulinemia. Interestingly, HAART-treated rats showed reduced size of pancreatic islets that was not seen in BSO-exposed rats. In vitro studies showed that nelfinavir, alone and in combination with HAART, induced oxidative stress and decreased glucose-induced insulin production in INS-1 cells. Suppressed insulin production was restored in cells coexposed to either BSO or thymoquinone. Our findings demonstrated that chronic HAART may increase serum insulin levels by dysregulating both insulin production by beta cells and insulin action at the periphery. These deleterious effects may be prevented by dietary supplementation with BSO.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Antiretroviral Therapy, Highly Active/adverse effects ; Benzoquinones/pharmacology ; Blood Glucose/analysis ; Cholesterol/blood ; HIV Protease Inhibitors/toxicity ; Hyperinsulinism/chemically induced ; Hyperinsulinism/drug therapy ; Insulin/blood ; Islets of Langerhans/drug effects ; Nelfinavir/toxicity ; Nigella sativa ; Phytotherapy ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism
Chemical Substances	Antioxidants ; Benzoquinones ; Blood Glucose ; HIV Protease Inhibitors ; Insulin ; Reactive Oxygen Species ; Cholesterol (97C5T2UQ7J) ; Nelfinavir (HO3OGH5D7I) ; thymoquinone (O60IE26NUF)
Language	English
Publishing date	2009-04-01
Publishing country	Canada
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/Y09-014
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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito