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  1. Article: Metformin Reduces the Progression of Atherogenesis by Regulating the Sestrin2-mTOR Pathway in Obese and Diabetic Rats.

    Sundararajan, Saravanakumar / Jayachandran, Isaivani / Pandey, Gautam Kumar / Venkatesan, Saravanakumar / Rajagopal, Anusha / Gokulakrishnan, Kuppan / Balasubramanyam, Muthuswamy / Mohan, Viswanathan / Manickam, Nagaraj

    Journal of lipid and atherosclerosis

    2023  Volume 12, Issue 3, Page(s) 290–306

    Abstract: Objective: In previous research, we found that Sestrin2 has a strong association with plasma atherogenicity and combats the progression of atherogenesis by regulating the AMPK-mTOR pathway. Metformin, an activator of AMPK, is widely used as a first-line ...

    Abstract Objective: In previous research, we found that Sestrin2 has a strong association with plasma atherogenicity and combats the progression of atherogenesis by regulating the AMPK-mTOR pathway. Metformin, an activator of AMPK, is widely used as a first-line therapy for diabetes, but its role in preventing atherosclerosis and cardiac outcomes is unclear. Hence, we aimed to assess the effect of metformin on preventing atherosclerosis and its regulatory role in the Sestrin2-AMPK -mTOR pathway in obese/diabetic rats.
    Methods: Animals were fed a high-fat diet to induce obesity, administered streptozotocin to induce diabetes, and then treated with metformin (150 mg/kg body weight) for 14 weeks. Aorta and heart tissues were analyzed for Sestrin2 status by western blotting and immunohistochemistry, AMPK and mTOR activities were investigated using western blotting, and atherogenicity-related events were evaluated using reverse transcription quantitative polymerase chain reaction and histology.
    Results: Obese and diabetic rats showed significant decrease in Sestrin2 levels and AMPK activity, accompanied by increased mTOR activity in the heart and aorta tissues. Metformin treatment significantly restored Sestrin2 and AMPK levels, reduced mTOR activity, and restored the altered expression of inflammatory markers and adhesion molecules in obese and diabetic rats to normal levels. A histological analysis of samples from obese and diabetic rats showed atherosclerotic lesions both in aorta and heart tissues. The metformin-treated rats showed a decrease in atherosclerotic lesions, cardiac hypertrophy, and cardiomyocyte degeneration.
    Conclusion: This study presents further insights into the beneficial effects of metformin and its protective role against atherosclerosis through regulation of the Sestrin2-AMPK-mTOR pathway.
    Language English
    Publishing date 2023-09-06
    Publishing country Korea (South)
    Document type Journal Article
    ZDB-ID 3016001-7
    ISSN 2288-2561 ; 2287-2892
    ISSN (online) 2288-2561
    ISSN 2287-2892
    DOI 10.12997/jla.2023.12.3.290
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin

    Gokulakrishnan, Kuppan / Pandey, Gautam Kumar / Sathishkumar, Chandrakumar / Sundararajan, Saravanakumar / Durairaj, Prabhu / Manickam, Nagaraj / Mohan, Viswanathan / Balasubramanyam, Muthuswamy

    Molecular biology reports. 2021 May, v. 48, no. 5

    2021  

    Abstract: A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the ... ...

    Abstract A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.
    Keywords adipocytes ; adipose tissue ; blood serum ; enzyme-linked immunosorbent assay ; genes ; glucose ; glucose tolerance tests ; high fat diet ; inflammation ; insulin resistance ; insulin tolerance test ; interleukin-6 ; lipids ; males ; metformin ; molecular biology ; protein synthesis ; quantitative polymerase chain reaction ; therapeutics ; vitamin A
    Language English
    Dates of publication 2021-05
    Size p. 4093-4106.
    Publishing place Springer Netherlands
    Document type Article
    ZDB-ID 186544-4
    ISSN 1573-4978 ; 0301-4851
    ISSN (online) 1573-4978
    ISSN 0301-4851
    DOI 10.1007/s11033-021-06420-y
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    In stock of ZB MED Bonn / Germany

    Z 78/728: Show issues

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  3. Article ; Online: Asymmetric dimethylarginine (ADMA) accelerates renal cell fibrosis under high glucose condition through NOX4/ROS/ERK signaling pathway.

    Jayachandran, Isaivani / Sundararajan, Saravanakumar / Venkatesan, Saravanakumar / Paadukaana, Sairaj / Balasubramanyam, Muthuswamy / Mohan, Viswanathan / Manickam, Nagaraj

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 16005

    Abstract: We previously reported that the circulatory level of Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, was increased in diabetic kidney disease patients. However, the mechanism and the role of ADMA in ... ...

    Abstract We previously reported that the circulatory level of Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, was increased in diabetic kidney disease patients. However, the mechanism and the role of ADMA in diabetic kidney injury remain unclear. Hence, our principal aim is to investigate the causal role of ADMA in the progression of renal cell fibrosis under high glucose (HG) treatment and to delineate its signaling alterations in kidney cell injury. High Glucose/ADMA significantly increased fibrotic events including cell migration, invasion and proliferation along with fibrotic markers in the renal cells; whereas ADMA inhibition reversed the renal cell fibrosis. To delineate the central role of ADMA induced fibrotic signaling pathway and its downstream signaling, we analysed the expression levels of fibrotic markers, NOX4, ROS and ERK activity by using specific inhibitors and genetic manipulation techniques. ADMA stimulated the ROS generation along with a significant increase in NOX4 and ERK activity. Further, we observed that ADMA activated NOX-4 and ERK are involved in the extracellular matrix proteins accumulation. Also, we observed that ADMA induced ERK1/2 phosphorylation was decreased after NOX4 silencing. Our study mechanistically demonstrates that ADMA is involved in the progression of kidney cell injury under high glucose condition by targeting coordinated complex mechanisms involving the NOX4- ROS-ERK pathway.
    MeSH term(s) Animals ; Arginine/adverse effects ; Arginine/analogs & derivatives ; Cell Line ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Diabetic Retinopathy/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibrosis ; Glucose/adverse effects ; Kidney/cytology ; Kidney/metabolism ; Kidney/pathology ; MAP Kinase Signaling System/drug effects ; Mesangial Cells/cytology ; Mesangial Cells/metabolism ; Mesangial Cells/pathology ; Models, Biological ; NADPH Oxidase 4/metabolism ; Rats ; Reactive Oxygen Species/metabolism
    Chemical Substances Reactive Oxygen Species ; N,N-dimethylarginine (63CV1GEK3Y) ; Arginine (94ZLA3W45F) ; NADPH Oxidase 4 (EC 1.6.3.-) ; Nox4 protein, rat (EC 1.6.3.-) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2020-09-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-72943-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin.

    Gokulakrishnan, Kuppan / Pandey, Gautam Kumar / Sathishkumar, Chandrakumar / Sundararajan, Saravanakumar / Durairaj, Prabhu / Manickam, Nagaraj / Mohan, Viswanathan / Balasubramanyam, Muthuswamy

    Molecular biology reports

    2021  Volume 48, Issue 5, Page(s) 4093–4106

    Abstract: A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the ... ...

    Abstract A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.
    MeSH term(s) 3T3-L1 Cells ; Adipocytes/drug effects ; Adipocytes/metabolism ; Adipose Tissue/metabolism ; Animals ; Diet, High-Fat/adverse effects ; Glucose/pharmacology ; Hypoglycemic Agents/administration & dosage ; Inflammation/drug therapy ; Inflammation/metabolism ; Insulin Resistance ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Metformin/administration & dosage ; Mice ; Palmitates/pharmacology ; Rats ; Rats, Wistar ; Retinol-Binding Proteins, Plasma/genetics ; Retinol-Binding Proteins, Plasma/metabolism ; Signal Transduction/drug effects ; Vildagliptin/administration & dosage
    Chemical Substances Hypoglycemic Agents ; Membrane Proteins ; Palmitates ; Rbp4 protein, mouse ; Rbp4 protein, rat ; Retinol-Binding Proteins, Plasma ; STRA6 protein, rat ; Stra6 protein, mouse ; Metformin (9100L32L2N) ; Vildagliptin (I6B4B2U96P) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-05-26
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 186544-4
    ISSN 1573-4978 ; 0301-4851
    ISSN (online) 1573-4978
    ISSN 0301-4851
    DOI 10.1007/s11033-021-06420-y
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1140: 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)

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  5. Article ; Online: Sestrin2 regulates monocyte activation through AMPK-mTOR nexus under high-glucose and dyslipidemic conditions.

    Sundararajan, Saravanakumar / Jayachandran, Isaivani / Balasubramanyam, Muthuswamy / Mohan, Viswanathan / Venkatesan, Balachandar / Manickam, Nagaraj

    Journal of cellular biochemistry

    2018  Volume 120, Issue 5, Page(s) 8201–8213

    Abstract: The vicious cycle between hyperinsulinemia and insulin resistance results in the progression of atherosclerosis in the vessel wall. The complex interaction between hyperglycemia and lipoprotein abnormalities promotes the development of atherogenesis. In ... ...

    Abstract The vicious cycle between hyperinsulinemia and insulin resistance results in the progression of atherosclerosis in the vessel wall. The complex interaction between hyperglycemia and lipoprotein abnormalities promotes the development of atherogenesis. In the early phase of atherosclerosis, macrophage-derived foam cells play an important role in vascular remodeling. Mechanistic target of rapamycin (mTOR) signaling pathway has been identified to play an essential role in the initiation, progression, and complication of atherosclerosis. Recently sestrin2, an antioxidant, was shown to modulate TOR activity and thereby regulating glucose and lipid metabolism. But the role of sestrin2 in monocyte activation is still not clearly understood. Hence, this study is focussed on investigating the role of sestrin2 in monocyte activation under hyperglycemic and dyslipidemic conditions. High-glucose and oxidized low-density lipoprotein (LDL) treatments mediated proinflammatory cytokine production (M1) with a concomitant decrease in the anti-inflammatory cytokine (M2) levels in human monocytic THP1 cells. Both glucose and oxidized LDL (OxLDL) in a dose and time-dependent manner increased the mTOR activation with a marked reduction in the levels of pAMPK and sestrin2 expression. Both high-glucose and OxLDL treatment increased foam cell formation and adhesion of THP1 cells to endothelial cells. Experiments employing activator or inhibitor of adenosine monophosphate kinase (AMPK) as well as overexpression or silencing of sestrin2 indicated that high-glucose mediated monocyte polarization and adhesion of monocytes to the endothelial cells were appeared to be programmed via sestrin2-AMPK-mTOR nexus. Our results evidently suggest that sestrin2 plays a major role in regulating monocyte activation via the AMPK-mTOR-pathway under diabetic and dyslipidemic conditions and also AMPK regulates sestrin2 in a feedback mechanism.
    Language English
    Publishing date 2018-11-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.28102
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1114: 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)

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  6. Article ; Online: Association of circulatory asymmetric dimethylarginine (ADMA) with diabetic nephropathy in Asian Indians and its causative role in renal cell injury.

    Jayachandran, Isaivani / Sundararajan, Saravanakumar / Paramasivam, Prabu / Venkatesan, Balachandar / Subramanian, Shanthirani C / Balasubramanyam, Muthuswamy / Mohan, Viswanathan / Manickam, Nagaraj

    Clinical biochemistry

    2017  Volume 50, Issue 15, Page(s) 835–842

    Abstract: Aim: Asymmetric dimethylarginine (ADMA) is involved in the regulation of nitric oxide synthesis and in the maintenance of vascular tone and structure. But the role and status of ADMA in diabetes induced kidney injury is not clear. Hence this study is ... ...

    Abstract Aim: Asymmetric dimethylarginine (ADMA) is involved in the regulation of nitric oxide synthesis and in the maintenance of vascular tone and structure. But the role and status of ADMA in diabetes induced kidney injury is not clear. Hence this study is investigating the role of ADMA in the progression of kidney injury and its circulatory status in Asian Indians with and without diabetic nephropathy.
    Methods: Recruited study subjects were divided into normal glucose tolerance (NGT), type 2 diabetes mellitus (T2DM) and T2DM with micro or macroalbuminuria. Albuminuria was calculated using urinary albumin and creatinine ratio (UACR). ADMA was measured using ELISA. Kidney cell damage in terms of fibrotic markers and ADMA metabolism in terms of DDAH activity were investigated in kidney fibroblasts and mesangial cells.
    Results: There was a significant elevation in plasma ADMA levels in micro and macroalbuminuric diabetic patients. We found a significant positive correlation between ADMA and UACR, serum creatinine, HbA1C and fasting plasma glucose. A cut-off value of ADMA, 0.666μM/l had a sensitivity and specificity of 70.0% and 65.6%, respectively for detecting diabetic nephropathy. DDAH activity was significantly decreased and fibrotic markers such as fibronectin and α-SMA were significantly increased upon high glucose and ADMA treatment.
    Conclusion: We are suggesting a causative role of ADMA in the development of kidney injury in terms of renal fibrosis and also a cut point of 0.666μM/l of plasma ADMA level appears to be a predictive risk threshold for diabetic nephropathy in south Asian Indian population.
    MeSH term(s) Adult ; Albuminuria/blood ; Albuminuria/urine ; Animals ; Arginine/analogs & derivatives ; Asian Continental Ancestry Group ; Biomarkers/blood ; Biomarkers/urine ; Cell Line ; Creatinine/blood ; Creatinine/urine ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/ethnology ; Diabetes Mellitus, Type 2/urine ; Diabetic Nephropathies/blood ; Diabetic Nephropathies/ethnology ; Diabetic Nephropathies/urine ; Female ; Fibroblasts/metabolism ; Glomerular Mesangium/injuries ; Glomerular Mesangium/metabolism ; Glycated Hemoglobin A/metabolism ; Humans ; India/ethnology ; Male ; Middle Aged ; Rats
    Chemical Substances Biomarkers ; Glycated Hemoglobin A ; hemoglobin A1c protein, human ; N,N-dimethylarginine (63CV1GEK3Y) ; Arginine (94ZLA3W45F) ; Creatinine (AYI8EX34EU)
    Language English
    Publishing date 2017-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 390372-2
    ISSN 1873-2933 ; 0009-9120
    ISSN (online) 1873-2933
    ISSN 0009-9120
    DOI 10.1016/j.clinbiochem.2017.05.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 624: 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)

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