57 results on '"Vijayakumar Sukumaran"'
Search Results
2. Liraglutide treatment improves the coronary microcirculation in insulin resistant Zucker obese rats on a high salt diet
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Vijayakumar Sukumaran, Hirotsugu Tsuchimochi, Takashi Sonobe, Mark T. Waddingham, Mikiyasu Shirai, and James T. Pearson
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Endothelial dysfunction ,Inflammation ,Liraglutide ,Nitric oxide ,Oxidative stress ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Background Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). Methods Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50–350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. Results We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (
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- 2020
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3. Vitamin D and Its Potential Interplay With Pain Signaling Pathways
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Abdella M. Habib, Karim Nagi, Nagendra Babu Thillaiappan, VijayaKumar Sukumaran, and Saghir Akhtar
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nociception ,DRG ,VDR ,NGF ,EGFR ,GDNF ,Immunologic diseases. Allergy ,RC581-607 - Abstract
About 50 million of the U.S. adult population suffer from chronic pain. It is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ~20% of the sufferers derive no benefit. Vitamin D, known for its role in calcium homeostasis and bone metabolism, is thought to be of clinical benefit in treating chronic pain without the side-effects of currently available analgesics. A strong correlation between hypovitaminosis D and incidence of bone pain is known. However, the potential underlying mechanisms by which vitamin D might exert its analgesic effects are poorly understood. In this review, we discuss pathways involved in pain sensing and processing primarily at the level of dorsal root ganglion (DRG) neurons and the potential interplay between vitamin D, its receptor (VDR) and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors. We also discuss how vitamin D/VDR might influence immune cells and pain sensitization as well as review the increasingly important topic of vitamin D toxicity. Further in vitro and in vivo experimental studies will be required to study these potential interactions specifically in pain models. Such studies could highlight the potential usefulness of vitamin D either alone or in combination with existing analgesics to better treat chronic pain.
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- 2020
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4. Ghrelin and vascular protection
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James T Pearson, Mikiyasu Shirai, Vijayakumar Sukumaran, Cheng-Kun Du, Hirotsugu Tsuchimochi, Takashi Sonobe, Mark T Waddingham, Rajesh Katare, and Daryl O Schwenke
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ghrelin ,ghs-r1a ,vasodilation ,angiogenesis ,inflammation ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Physiology ,QP1-981 - Abstract
Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis.
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- 2019
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5. Ghrelin Pre-treatment Attenuates Local Oxidative Stress and End Organ Damage During Cardiopulmonary Bypass in Anesthetized Rats
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Vijayakumar Sukumaran, Hirotsugu Tsuchimochi, Yutaka Fujii, Hiroshi Hosoda, Kenji Kangawa, Tsuyoshi Akiyama, Mikiyasu Shirai, Eisuke Tatsumi, and James T. Pearson
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ghrelin ,inflammation ,organ damage ,oxidative stress ,cardiopulmonary bypass ,Physiology ,QP1-981 - Abstract
Cardiopulmonary bypass (CPB) induced systemic inflammation significantly contributes to the development of postoperative complications, including respiratory failure, myocardial, renal and neurological dysfunction and ultimately can lead to failure of multiple organs. Ghrelin is a small endogenous peptide with wide ranging physiological effects on metabolism and cardiovascular regulation. Herein, we investigated the protective effects of ghrelin against CPB-induced inflammatory reactions, oxidative stress and acute organ damage. Adult male Sprague Dawley rats randomly received vehicle (n = 5) or a bolus of ghrelin (150 μg/kg, sc, n = 5) and were subjected to CPB for 4 h (protocol 1). In separate rats, ghrelin pre-treatment (protocol 2) was compared to two doses of ghrelin (protocol 3) before and after CPB for 2 h followed by recovery for 2 h. Blood samples were taken prior to CPB, and following CPB at 2 h and 4 h. Organ nitrosative stress (3-nitrotyrosine) was measured by Western blotting. CPB induced leukocytosis with increased plasma levels of tumor necrosis factor-α and interleukin-6 indicating a potent inflammatory response. Ghrelin treatment significantly reduced plasma organ damage markers (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase) and protein levels of 3-nitrotyrosine, particularly in the brain, lung and liver, but only partly suppressed inflammatory cell invasion and did not reduce proinflammatory cytokine production. Ghrelin partially attenuated the CPB-induced elevation of epinephrine and to a lesser extent norepinephrine when compared to the CPB saline group, while dopamine levels were completely suppressed. Ghrelin treatment sustained plasma levels of reduced glutathione and decreased glutathione disulphide when compared to CPB saline rats. These results suggest that even though ghrelin only partially inhibited the large CPB induced increase in catecholamines and organ macrophage infiltration, it reduced oxidative stress and subsequent cell damage. Pre-treatment with ghrelin might provide an effective adjunct therapy for preventing widespread CPB induced organ injury.
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- 2018
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6. Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis
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Vijayakumar Sukumaran, Kenichi Watanabe, Punniyakoti T. Veeraveedu, Narasimman Gurusamy, Meilei Ma, Rajarajan A. Thandavarayan, Arun Prasath Lakshmanan, Ken'ichi Yamaguchi, Kenji Suzuki, Makoto Kodama
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Biology (General) ,QH301-705.5 - Abstract
Studies have demonstrated that angiotensin II has been involved in immune and inflammatory responses which might contribute to the pathogenesis of immune-mediated diseases. Recent evidence suggests that oxidative stress may play a role in myocarditis. Here, we investigated whether olmesartan, an AT1R antagonist protects against experimental autoimmune myocarditis (EAM) by suppression of oxidative stress, endoplasmic reticulum (ER) stress and inflammatory cytokines. EAM was induced in Lewis rats by immunization with porcine cardiac myosin, were divided into two groups and treated with either olmesartan (10 mg/kg/day) or vehicle for a period of 21 days. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Treatment with olmesartan attenuated the myocardial mRNA expressions of proinflammatory cytokines, [Interleukin (IL)-1β, monocyte chemoattractant protein-1, tumor necrosis factor-α and interferon-γ)] and the protein expression of tumor necrosis factor-α compared with that of vehicle-treated rats. Myocardial protein expressions of AT1R, NADPH oxidase subunits (p47phox, p67phox, gp91phox) and the expression of markers of oxidative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), and the cardiac apoptosis were also significantly decreased by the treatment with olmesartan compared with those of vehicle-treated rats. Furthermore, olmesartan treatment down-regulated the myocardial expressions of glucose regulated protein-78, growth arrest and DNA damage-inducible gene, caspase-12, phospho-p38 mitogen-activated protein kinase (MAPK) and phospho-JNK. These findings suggest that olmesartan protects against EAM in rats, at least in part via suppression of oxidative stress, ER stress and inflammatory cytokines.
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- 2011
7. Cardioprotective Effects of Telmisartan against Heart Failure in Rats Induced By Experimental Autoimmune Myocarditis through the Modulation of Angiotensin-Converting Enzyme-2/Angiotensin 1-7/Mas Receptor Axis
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Vijayakumar Sukumaran, Punniyakoti T. Veeraveedu, Narasimman Gurusamy, Ken'ichi Yamaguchi, Arun Prasath Lakshmanan, Meilei Ma, Kenji Suzuki, Makoto Kodama, Kenichi Watanabe
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Biology (General) ,QH301-705.5 - Abstract
Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.
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- 2011
8. Experimental Assessment of Cardiovascular Physiology in the Chick Embryo
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Vijayakumar Sukumaran, Onur Mutlu, Mohammad Murtaza, Rawia Alhalbouni, Benjamin Dubansky, and Huseyin C Yalcin
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Developmental Biology - Published
- 2023
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9. Understanding diabetes-induced cardiomyopathy from the perspective of renin angiotensin aldosterone system
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Vijayakumar Sukumaran, Narasimman Gurusamy, Huseyin C. Yalcin, and Sundararajan Venkatesh
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Inflammation ,Receptors, Angiotensin ,Diabetic Cardiomyopathies ,Physiology ,Angiotensin II ,Clinical Biochemistry ,Diabetic cardiomyopathy ,Peptidyl-Dipeptidase A ,musculoskeletal system ,complex mixtures ,Renin-Angiotensin System ,Oxidative Stress ,Oxidative stress ,Physiology (medical) ,cardiovascular system ,Autophagy ,Animals ,Humans ,Rennin angiotensin aldosterone system ,Obesity ,cardiovascular diseases ,Mitochondrial dysfunction - Abstract
Experimental and clinical evidence suggests that diabetic subjects are predisposed to a distinct cardiovascular dysfunction, known as diabetic cardiomyopathy (DCM), which could be an autonomous disease independent of concomitant micro and macrovascular disorders. DCM is one of the prominent causes of global morbidity and mortality and is on a rising trend with the increase in the prevalence of diabetes mellitus (DM). DCM is characterized by an early left ventricle diastolic dysfunction associated with the slow progression of cardiomyocyte hypertrophy leading to heart failure, which still has no effective therapy. Although the well-known "Renin Angiotensin Aldosterone System (RAAS)" inhibition is considered a gold-standard treatment in heart failure, its role in DCM is still unclear. At the cellular level of DCM, RAAS induces various secondary mechanisms, adding complications to poor prognosis and treatment of DCM. This review highlights the importance of RAAS signaling and its major secondary mechanisms involving inflammation, oxidative stress, mitochondrial dysfunction, and autophagy, their role in establishing DCM. In addition, studies lacking in the specific area of DCM are also highlighted. Therefore, understanding the complex role of RAAS in DCM may lead to the identification of better prognosis and therapeutic strategies in treating DCM. Qatar National Research Fund - Rapid Response Call
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- 2021
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10. β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto–Kakizaki rat
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Hirotsugu Tsuchimochi, Takashi Sonobe, Keiji Umetani, Amanda J. Edgley, Mikiyasu Shirai, Dong Yun Zhan, Tadakatsu Inagaki, Jennifer P. Ngo, Yutaka Fujii, Hamish P Thambyah, James T. Pearson, Yi Ching Chen, Mark T. Waddingham, Cheng-Kun Du, Connie P. C. Ow, Darren J. Kelly, and Vijayakumar Sukumaran
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Male ,0301 basic medicine ,medicine.medical_specialty ,Adrenergic beta-Antagonists ,030204 cardiovascular system & hematology ,Coronary Angiography ,Nitric Oxide ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Sodium Chloride, Dietary ,Endothelial dysfunction ,Salt intake ,Microvessel ,Metoprolol ,business.industry ,Coronary flow reserve ,General Medicine ,medicine.disease ,Adrenergic beta-1 Receptor Antagonists ,Angiotensin II ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Hypertension ,Carvedilol ,Endothelium, Vascular ,Insulin Resistance ,business ,Endothelin receptor ,medicine.drug - Abstract
A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.
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- 2021
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11. P0978THE EFFECTS OF CHRONIC DAPAGLIFLOZIN TREATMENT ON THE RENAL MICROVASCULATURE IN A RAT MODEL OF TYPE 2 DIABETES
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Hirotsugu Tsuchimochi, Vijayakumar Sukumaran, Hiroshi Hosoda, Jennifer P. Ngo, James T. Pearson, Akihiro Fujiwara, Roger G. Evans, Cheng-Kun Du, and Connie P. C. Ow
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Transplantation ,chemistry.chemical_compound ,chemistry ,Nephrology ,business.industry ,Rat model ,Medicine ,Type 2 diabetes ,Dapagliflozin ,Pharmacology ,business ,medicine.disease - Abstract
Background and Aims Chronic kidney disease (CKD) is an ever-growing concern and CKD associated with diabetes accounted for ∼ 35% of new cases of end-stage renal failure. Clinical trials with insulin-independent sodium-glucose co-transporter 2 (SGLT2) inhibitors not only showed significant improvements in hyperglycemia and thus renal damage, but also reduced the risk of adverse cardiovascular events. Microvessels supply local tissue oxygen demands and are important controllers of regional perfusion. Endothelial dysfunction has been posited to be an important factor driving the pathogenesis of diabetic nephropathy, largely through impaired eNOS activity and thus reduced nitric oxide bioavailability. Thus, we aim to determine the effects of SGLT2 inhibition on vasodilator function in the renal vasculature. We hypothesize that rats chronically treated with dapagliflozin, a SGLT2 inhibitor, improves renal endothelial function and the microvessels are better able to maintain perfusion in response to the inhibition of nitric oxide synthase and prostaglandin blockade. Method Male Zucker fatty diabetic rats (8 wk old), a model of type 2 diabetes, were given daily oral gavage of 1 mg/kg dapagliflozin or its vehicle for up to 22 wks of age (n=6/group). Renal excretory function, glomerular filtration rate (GFR) and indices of renal injury was assessed before treatment and after every 4 wks up until 22 wks of age. GFR was assessed via transcutaneous clearance of FITC-sinistrin. Vasodilator function of the renal microvasculature was assessed via X-ray microangiography. We conducted successive imaging of the microvessels before and during infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) which facilitated the assessment of endothelium dependent and independent dilation respectively. After which, rats were given successive boluses of L-NAME and indomethacin to assess the vasodilatory function of the microvasculature independent of nitric oxide and prostaglandins respectively. These inhibitors were given under the conditions of SNP clamp which allowed for us to titrate the blood pressure to baseline levels. Lastly, we assessed the ability of endothelium hyperpolarizing factors (EDHFs) to maintain microvascular perfusion when SNP infusion ceased and an infusion of ACh commenced while still under the effects of L-NAME and indomethacin. Results As expected, dapagliflozin alleviated hyperglycemia across the treatment period. There was a tendency for dapagliflozin to ameliorate the decline of GFR, although this apparent effect was not statistically significant. Dapagliflozin did not appear to improve indices of renal injury. Treatment with dapagliflozin alleviated polyuria but did not appear to have an impact on urine osmolarity or sodium excretion. The responses (vessel diameter) of renal microvessels to ACh and SNP was greater in dapagliflozin than in vehicle fed rats. The microvessels of vehicle fed rats appeared to undergo relative constriction in response to L-NAME and indomethacin even under the effects of SNP clamp. In contrast, microvessels of dapagliflozin fed rats appeared to be relatively well-perfused after NOS and COX blockade. This suggests that dapagliflozin may improve endothelial dysfunction commonly associated with diabetic nephropathy. Following NOS and COX blockade, ACh was infused in rats to determine the status of vasodilatory function mediated by EDHFs. The microvessels in diabetic rats did not appear to be dilated after infusion of ACh, suggesting that vasodilatory effects of EDHFs on the vasculature is diminished in diabetic rats. Dapagliflozin appeared to improve this effect in that the renal microvessels were dilated even when NOS and COX production was blocked/inhibited. Conclusion Chronic treatment of dapagliflozin may improve endothelial dysfunction and thus retard the progression of diabetic nephropathy in a rat model of type 2 diabetes.
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- 2020
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12. Vitamin D and Its Potential Interplay With Pain Signaling Pathways
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Saghir Akhtar, Vijayakumar Sukumaran, Karim Nagi, Abdella M. Habib, and Nagendra Babu Thillaiappan
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,EGFR ,Immunology ,Analgesic ,Pain ,Review ,vitamin D toxicity ,Bioinformatics ,Calcitriol receptor ,03 medical and health sciences ,0302 clinical medicine ,Neurotrophic factors ,Ganglia, Spinal ,Nerve Growth Factor ,medicine ,Glial cell line-derived neurotrophic factor ,Vitamin D and neurology ,Animals ,Humans ,Immunology and Allergy ,Glial Cell Line-Derived Neurotrophic Factor ,nociception ,Vitamin D ,Bone pain ,VDR ,Neurons ,NGF ,Analgesics ,biology ,business.industry ,Chronic pain ,opioids ,medicine.disease ,GDNF ,ErbB Receptors ,030104 developmental biology ,Opioid ,DRG ,Receptors, Opioid ,biology.protein ,Receptors, Calcitriol ,medicine.symptom ,lcsh:RC581-607 ,business ,Signal Transduction ,030215 immunology ,medicine.drug - Abstract
About 50 million of the U.S. adult population suffer from chronic pain. It is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ~20% of the sufferers derive no benefit. Vitamin D, known for its role in calcium homeostasis and bone metabolism, is thought to be of clinical benefit in treating chronic pain without the side-effects of currently available analgesics. A strong correlation between hypovitaminosis D and incidence of bone pain is known. However, the potential underlying mechanisms by which vitamin D might exert its analgesic effects are poorly understood. In this review, we discuss pathways involved in pain sensing and processing primarily at the level of dorsal root ganglion (DRG) neurons and the potential interplay between vitamin D, its receptor (VDR) and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors. We also discuss how vitamin D/VDR might influence immune cells and pain sensitization as well as review the increasingly important topic of vitamin D toxicity. Further in vitro and in vivo experimental studies will be required to study these potential interactions specifically in pain models. Such studies could highlight the potential usefulness of vitamin D either alone or in combination with existing analgesics to better treat chronic pain.
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- 2020
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13. EFFECTS OF A GLUCAGON LIKE PEPTIDE-1 AGONIST AND RHO-KINASE INHIBITOR ON PULMONARY AND RIGHT VENTRICLE FUNCTION IN PULMONARY HYPERTENSIVE RATS WITH AND WITHOUT INSULIN RESISTANCE
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Connie P. C. Ow, Huiling Jin, Jennifer P. Ngo, Takeshi Ogo, Hatsue-Ishibash Ueda, Hisashi Maeda, Vijayakumar Sukumaran, Hirotsugu Tsuchimochi, Mark T. Waddingham, James T. Pearson, Takashi Sonobe, and Mikiyasu Shirai
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Agonist ,medicine.medical_specialty ,Physiology ,medicine.drug_class ,business.industry ,medicine.disease ,Glucagon-like peptide-1 ,medicine.anatomical_structure ,Insulin resistance ,Endocrinology ,Ventricle ,Rho kinase inhibitor ,Internal medicine ,Internal Medicine ,medicine ,Cardiology and Cardiovascular Medicine ,business ,Function (biology) - Published
- 2021
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14. Liraglutide treatment improves the coronary microcirculation in insulin resistant Zucker obese rats on a high salt diet
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Takashi Sonobe, Vijayakumar Sukumaran, Mikiyasu Shirai, Mark T. Waddingham, James T. Pearson, and Hirotsugu Tsuchimochi
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Male ,medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Endocrinology, Diabetes and Metabolism ,Vasodilation ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Incretins ,Glucagon-Like Peptide-1 Receptor ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Enos ,Internal medicine ,Coronary Circulation ,medicine ,Animals ,Hypoglycemic Agents ,Obesity ,Endothelial dysfunction ,Sodium Chloride, Dietary ,030304 developmental biology ,Original Investigation ,Inflammation ,0303 health sciences ,biology ,Ventricular Remodeling ,business.industry ,Microcirculation ,Nitric oxide ,Liraglutide ,biology.organism_classification ,medicine.disease ,Rats, Zucker ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,Blood pressure ,Oxidative stress ,lcsh:RC666-701 ,Heart failure ,Hypertension ,Metabolic syndrome ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,Soluble guanylyl cyclase ,business - Abstract
Background Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). Methods Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50–350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. Results We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably. Conclusions In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose.
- Published
- 2019
15. Ghrelin and vascular protection
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Mikiyasu Shirai, Hirotsugu Tsuchimochi, Daryl O. Schwenke, Vijayakumar Sukumaran, Rajesh Katare, Takashi Sonobe, James T. Pearson, Cheng-Kun Du, and Mark T. Waddingham
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medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Angiogenesis ,Mini Review ,media_common.quotation_subject ,medicine.medical_treatment ,Vasodilation ,Inflammation ,lcsh:Physiology ,angiogenesis ,Immune system ,Internal medicine ,medicine ,Glucose homeostasis ,vasodilation ,media_common ,lcsh:QP1-981 ,business.industry ,digestive, oral, and skin physiology ,ghs-r1a ,Appetite ,General Medicine ,Endocrinology ,Cytokine ,inflammation ,lcsh:RC666-701 ,ghrelin ,Ghrelin ,medicine.symptom ,business - Abstract
Ghrelin is a small peptide with important roles in the regulation of appetite, gut motility, glucose homeostasis as well as cardiovascular protection. This review highlights the role that acyl ghrelin plays in maintaining normal endothelial function by maintaining the balance of vasodilator-vasoconstrictor factors, inhibiting inflammatory cytokine production and immune cell recruitment to sites of vascular injury and by promoting angiogenesis.
- Published
- 2019
16. Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms
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Samar Shurbaji, Huseyin C. Yalcin, Vijayakumar Sukumaran, and Mahmoud Khatib A A Al-Ruweidi
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0301 basic medicine ,ACE inhibitors ,QH301-705.5 ,Cell ,Virulence ,Angiotensin-Converting Enzyme Inhibitors ,Review ,Disease ,030204 cardiovascular system & hematology ,Biology ,Bioinformatics ,Catalysis ,Virus ,Inorganic Chemistry ,shedding ,03 medical and health sciences ,chemistry.chemical_compound ,RAAS ,0302 clinical medicine ,medicine ,Humans ,Biology (General) ,Physical and Theoretical Chemistry ,Lung ,QD1-999 ,Molecular Biology ,Spectroscopy ,Kidney ,Aldosterone ,Host Microbial Interactions ,SARS-CoV-2 ,Organic Chemistry ,ACE-2 ,COVID-19 ,SARS-CoV ,Angiotensin-converting enzyme ,General Medicine ,Computer Science Applications ,angiotensin receptor blockers ,Chemistry ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,biology.protein ,ARDS ,Angiotensin-Converting Enzyme 2 ,Function (biology) - Abstract
The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.
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- 2021
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17. Diastolic dysfunction is initiated by cardiomyocyte impairment ahead of endothelial dysfunction due to increased oxidative stress and inflammation in an experimental prediabetes model
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Takeshi Ogo, Walter Paulus, Shahrooz Gaderi, Takashi Sonobe, Sarabjit S. Hansra, Mikiyasu Shirai, Darren J. Kelly, Keiji Umetani, Yi Ching Chen, Melissa Herwig, Daryl O. Schwenke, Amanda J. Edgley, James T. Pearson, Mark T. Waddingham, Vijayakumar Sukumaran, Kohki Aoyama, Andreas Mügge, Nazha Hamdani, Naoto Yagi, Detmar Kolijn, Hirotsugu Tsuchimochi, and Physiology
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0301 basic medicine ,Male ,Myofilament ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Myosin head ,0302 clinical medicine ,Diastole ,Superoxides ,Connectin ,Myocytes, Cardiac ,NADH, NADPH Oxidoreductases ,Endothelial dysfunction ,Phosphorylation ,biology ,Vasodilation ,Actin Cytoskeleton ,cardiovascular system ,Cytokines ,Titin ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Heart Ventricles ,macromolecular substances ,Myosins ,Nitric Oxide ,Prediabetic State ,03 medical and health sciences ,Multienzyme Complexes ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Molecular Biology ,Inflammation ,business.industry ,Hydrogen Peroxide ,medicine.disease ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Guanylate Cyclase ,biology.protein ,Endothelium, Vascular ,business ,Heart failure with preserved ejection fraction ,Soluble guanylyl cyclase ,Peptides ,Oxidative stress - Abstract
Coronary microvessel endothelial dysfunction and nitric oxide (NO) depletion contribute to elevated passive tension of cardiomyocytes, diastolic dysfunction and predispose the heart to heart failure with preserved ejection fraction. We examined if diastolic dysfunction at the level of the cardiomyocytes precedes coronary endothelial dysfunction in prediabetes. Further, we determined if myofilaments other than titin contribute to impairment. Utilizing synchrotron microangiography we found young prediabetic male rats showed preserved dilator responses to acetylcholine in microvessels. Utilizing synchrotron X-ray diffraction we show that cardiac relaxation and cross-bridge dynamics are impaired by myosin head displacement from actin filaments particularly in the inner myocardium. We reveal that increased PKC activity and mitochondrial oxidative stress in cardiomyocytes contributes to rho-kinase mediated impairment of myosin head extension to actin filaments, depression of soluble guanylyl cyclase/PKG activity and consequently stiffening of titin in prediabetes ahead of coronary endothelial dysfunction.
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- 2019
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18. Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet
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Mikiyasu Shirai, Takashi Sonobe, Vijayakumar Sukumaran, James T. Pearson, and Hirotsugu Tsuchimochi
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0301 basic medicine ,Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Renal function ,Vasodilation ,Blood Pressure ,Kidney ,Nitric Oxide ,Gene Expression Regulation, Enzymologic ,Glucagon-Like Peptide-1 Receptor ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Enos ,Internal medicine ,medicine ,Animals ,Endothelium ,Sodium Chloride, Dietary ,Pharmacology ,biology ,business.industry ,Macrophages ,Hemodynamics ,Gap Junctions ,Liraglutide ,medicine.disease ,biology.organism_classification ,Fibrosis ,Rats ,Rats, Zucker ,Vascular endothelial growth factor ,030104 developmental biology ,Endocrinology ,chemistry ,Cytoprotection ,Renal physiology ,Molecular Medicine ,Sodium nitroprusside ,business ,030217 neurology & neurosurgery ,Kidney disease ,medicine.drug ,Glomerular Filtration Rate - Abstract
Metabolic syndrome is a common risk factor in chronic kidney disease. We investigated whether liraglutide [(LIRA), a glucagon-like peptide-1 receptor (GLP-1R) agonist] treatment improved renal vascular function and renal remodeling in male Zucker rats on a high-salt diet (6% NaCl). Zucker lean (+/+) and obese (fa/fa) rats (8 weeks old) were treated with vehicle or LIRA (0.1 mg/kg per day) for 8 weeks on a high-salt diet. The glomerular filtration rate (GFR) was measured at 0 and 8 weeks using the fluorescein isothiocyanate/sinistrin method in conscious rats. We used X-ray microangiography to measure renal arterial vessel diameter (70-350 µm) and vessel number in vivo in anesthetized rats. Renal protein expression levels of nitrotyrosine, CD-68, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), transforming growth factor-β1, cyclooxygenase-2, and GLP-1R were assessed by western blotting. Renal gene expressions were determined by real-time polymerase chain reaction. In contrast to vehicle-treated rats, fa/fa-LIRA rats improved GFR, nitric oxide (NO)-mediated vasodilation in response to acetylcholine and sodium nitroprusside in small arterial vessels (
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- 2018
19. A slow cycling Lgr5 tumour population mediates basal cell carcinoma relapse after therapy
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Josep Tabernero, Gaëlle Lapouge, Adriana Sánchez-Danés, Cédric Blanpain, Audrey Brisebarre, Christine Dubois, Véronique Del Marmol, Eva Muñoz-Couselo, Jean-Christophe Larsimont, Vijayakumar Sukumaran, Mariano Suppa, and Mélanie Liagre
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Male ,0301 basic medicine ,Skin Neoplasms ,animal structures ,Pyridines ,Population ,Vismodegib ,Article ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,Recurrence ,Secondary Prevention ,medicine ,Animals ,Humans ,Anilides ,Cell Lineage ,Hedgehog Proteins ,Basal cell carcinoma ,education ,skin and connective tissue diseases ,Wnt Signaling Pathway ,Hedgehog ,education.field_of_study ,Multidisciplinary ,integumentary system ,business.industry ,fungi ,Wnt signaling pathway ,LGR5 ,Cancer ,Cell Differentiation ,Sciences bio-médicales et agricoles ,medicine.disease ,Smoothened Receptor ,Patched-1 Receptor ,Wnt Proteins ,Disease Models, Animal ,030104 developmental biology ,Withholding Treatment ,Carcinoma, Basal Cell ,Cancer research ,Female ,Neoplasm Recurrence, Local ,Smoothened ,business ,Hair Follicle ,medicine.drug - Abstract
Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2018
20. 4 糖尿病性臓器障害の基礎的検討 : 糖尿病性心筋症・腎症と小胞体ストレス(シンポジウム「糖尿病の合併症, 第699回新潟医学会)
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Arun, P Lakshmanan, Vivian, Soetikno, Flori, R Sari, Vijayakumar, Sukumaran, Vijayasree, V Giridharan, Rejina, Afrin, Somasundaram, Arumugam, Vengadesh, Karuppagounder, Rajarajan, A Thandavarayan, Vigneshwaran, Pitchaimani, and Remya, Sreedhar
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糖尿病性腎症 ,小胞体ストレス ,酸化ストレス ,diabetic nephropathy ,endoplasmic reticulum stress ,diabetic cardiomyopathy ,oxidative stress ,curcumin ,糖尿病性心筋症 ,クルクミン - Abstract
心臓・腎臓など糖尿病性臓器障害の進展は, AMP活性化プロテインキナーゼ(AMPK)と小胞体ストレスが関与する. AMPKと小胞体ストレスは, 糖尿病性臓器障害における新治療薬の標的となりうることが示唆される. 糖尿病性腎症モデルの腎臓では酸化ストレス・炎症・線維化・脂肪沈着が亢進している. クルクミンはこれらを改善し, 安価な糖尿病腎症の予防薬・治療薬となりうることが示唆される., Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) in patients starting renal replacement therapy and affects ~ 40 % of type 1 and type 2 diabetic patients. Hyperglycemia plays a key role in the pathogenesis of long-term complications in diabetes mellitus. This process is influenced by individual susceptibility (i.e. genetic determinants) and by accelerating factors such as hypertension, inflammation and dyslipidemia, all of which are able to stimulate generation of reactive oxygen species (ROS). The increased of ROS production causes tissue damage through 4 major mechanisms: (1) increased flux of glucose and other sugars through the polyol pathway; (2) increased intracellular formation of advanced glycation end products (AGEs) and its receptor; receptor for AGEs (RAGE) and its activating ligands; (3) activation of protein kinase C (PKC) isoforms; and (4) overactivity of the hexosamine pathway. The PKC signaling pathway is the postulate that has received the most attention lately. PKC activation is involved in the regulation of vascular permeability and contractility, endothelial cell activation and vasoconstriction, extracellular matrix (ECM) synthesis and turnover, abnormal angiogenesis, excessive apoptosis, leucocyte adhesion, abnormal growth factor signaling and cytokine action, as well as abnormal cell growth and angiogenesis, all of which are involved in the pathophysiology of diabetic vascular complications. There is growing evidence that abnormal lipid metabolism and renal accumulation of lipids play a role in the pathogenesis of DN. Sterol regulatory elemen-binding proteins (SREBPs) are transcription factors that regulate fatty acid and cholesterol synthesis. SREBPs belong to basic helix-loop-helix-leucine zipper family and activate the entire program of fatty acid and cholesterol synthesis in liver. Currently, there are three SREBPs isoforms that have been identified and characterized, namely, SREBP-1a, SREBP-1c, and SREBP-2. Multiple lines of evidence suggest that SREBP-1 and SREBP-2 have different relative effects on target genes. SREBP-1 preferentially activates genes involved in fatty acid and triglyceride synthesis, including Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), whereas SREBP-2 preferentially activates genes involved in cholesterol biosynthesis such as hydroxymethylglutaryl CoA synthase, hydroxymethylglutaryl CoA reductase, farnesyl diphosphate synthase, and squalene synthase. It has been demonstrated that there is an inverse correlation between 5' Adenosine monophosphate-activated protein kinase (AMPK) and SREBP-1c activity in hepatocytes and in livers of re-fed mice and ethanol-fed mice. In fact, AMPK is sufficient and necessary for the suppression of SREBP-1c proteolytic processing, nuclear translocation, and gene expression of target lipogenic enzymes in response to AMPK activators, such as polyphenols and metformin, in primary hepatocytes under conditions mimicking in vivo hyperglycemia and hyperinsulinemia. Curcumin is the major active constituent of turmeric, a yellow compound originally isolated from the plant Curcuma longa L. and has been used as a dietary spice and coloring agent in foods. It has a wide spectrum of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-obesity, and anticancer properties, prevents liver injury and kidney toxicity. We investigated the role of curcumin in experimental type 1 diabetic rats. Our results suggest that curcumin could ameliorate hyperglycemia, hyperlipidemia, inflammation and fibrosis in kidney tissues associated with DN which involved the dual blockade of both PKCα and PKCβ1 activities, reduced macrophage infiltration through the inhibition of NF-κB, and reduced renal triglyceride accumulation through the modulation of AMPK-SREBP pathway. Collectively, my present study provides data to support the role of curcumin in ameliorating DN in rats.
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- 2015
21. Azilsartan ameliorates diabetic cardiomyopathy in young db/db mice through the modulation of ACE-2/ANG 1-7/Mas receptor cascade
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Eisuke Tatsumi, Mikiyasu Shirai, James T. Pearson, Hirotsugu Tsuchimochi, and Vijayakumar Sukumaran
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0301 basic medicine ,Male ,medicine.medical_specialty ,Cardiac fibrosis ,Diabetic Cardiomyopathies ,Blood Pressure ,Mice, Transgenic ,030204 cardiovascular system & hematology ,Peptidyl-Dipeptidase A ,Biochemistry ,Proto-Oncogene Mas ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Atrial natriuretic peptide ,Fibrosis ,Internal medicine ,Diabetic cardiomyopathy ,Proto-Oncogene Proteins ,Azilsartan ,medicine ,Animals ,Pharmacology ,Oxadiazoles ,biology ,business.industry ,Angiotensin-converting enzyme ,medicine.disease ,Angiotensin II ,Peptide Fragments ,CTGF ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,biology.protein ,Benzimidazoles ,Angiotensin-Converting Enzyme 2 ,Angiotensin I ,business ,medicine.drug ,Signal Transduction - Abstract
Hyperglycemia up-regulates intracellular angiotensin II (ANG-II) production in cardiac myocytes. This study investigated the hemodynamic and metabolic effects of azilsartan (AZL) treatment in a mouse model of diabetic cardiomyopathy and whether the cardioprotective effects of AZL are mediated by the angiotensin converting enzyme (ACE)-2/ANG 1–7/Mas receptor (R) cascade. Control db/+ and db/db mice (n = 5 per group) were treated with vehicle or AZL (1 or 3 mg/kg/d oral gavage) from the age of 8 to 16 weeks. Echocardiography was then performed and myocardial protein levels of ACE-2, Mas R, AT 1 R, AT 2 R, osteopontin, connective tissue growth factor (CTGF), atrial natriuretic peptide (ANP) and nitrotyrosine were measured by Western blotting. Oxidative DNA damage and inflammatory markers were assessed by immunofluorescence of 8-hydroxy-2′-deoxyguanosine (8-OHdG), tumor necrosis factor (TNF)-α and interleukin 6 (IL-6). Compared with db/+ mice, the vehicle-treated db/db mice developed obesity, hyperglycemia, hyperinsulinemia and diastolic dysfunction along with cardiac hypertrophy and fibrosis. AZL treatment lowered blood pressure, fasting blood glucose and reduced peak plasma glucose during an oral glucose tolerance test. AZL-3 treatment resulted in a significant decrease in the expression of cytokines, oxidative DNA damage and cardiac dysfunction. Moreover, AZL-3 treatment significantly abrogated the downregulation of ACE-2 and Mas R protein levels in db/db mice. Furthermore, AZL treatment significantly reduced cardiac fibrosis, hypertrophy and their marker molecules (osteopontin, CTGF, TGF-β1 and ANP). Short-term treatment with AZL-3 reversed abnormal cardiac structural remodeling and partially improved glucose metabolism in db/db mice by modulating the ACE-2/ANG 1–7/Mas R pathway.
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- 2017
22. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation
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Doriana Pucci, Vijayakumar Sukumaran, Jean-Valery Berthe, Gaëlle Lapouge, Khalil Kass Youssef, Stein Aerts, Sylvain Brohée, Karine Bouvrée, Ornella Appelstein, Véronique Del Marmol, Jean-Christophe Larsimont, Cédric Blanpain, Isabelle Salmon, Sandrine Rorive, Sophie Dekoninck, and Bram Van de Sande
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Keratinocytes ,Cell signaling ,Epidermis (botany) ,Reverse Transcriptase Polymerase Chain Reaction ,Wnt signaling pathway ,Mice, Transgenic ,Cell Biology ,Biology ,Flow Cytometry ,Real-Time Polymerase Chain Reaction ,medicine.disease ,Immunohistochemistry ,Cell biology ,Mice ,Carcinoma, Basal Cell ,Neoplastic Stem Cells ,medicine ,Animals ,Basal cell carcinoma ,Progenitor cell ,Smoothened ,Hair Follicle ,Reprogramming ,Hedgehog ,beta Catenin - Abstract
Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/ β-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of β-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.
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- 2012
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23. Curcumin prevents diabetic cardiomyopathy in streptozotocin-induced diabetic rats: Possible involvement of PKC–MAPK signaling pathway
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Sayaka Mito, Flori R. Sari, Vijayakumar Sukumaran, Ritsuo Takagi, Masaki Nagata, Meilei Harima, Rajarajan Amirthalingam Thandavarayan, Arun Prasath Lakshmanan, Vivian Soetikno, Kenichi Watanabe, and Kenji Suzuki
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Male ,MAPK/ERK pathway ,medicine.medical_specialty ,Curcumin ,Diabetic Cardiomyopathies ,Heart Ventricles ,Pharmaceutical Science ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Diabetic cardiomyopathy ,Internal medicine ,medicine ,Animals ,Myocytes, Cardiac ,Protein kinase A ,Protein Kinase Inhibitors ,Protein kinase C ,Glutathione Peroxidase ,biology ,Kinase ,Hemodynamics ,Streptozotocin ,medicine.disease ,Fibrosis ,Rats ,Oxidative Stress ,Diabetes Mellitus, Type 1 ,Endocrinology ,chemistry ,Hyperglycemia ,biology.protein ,Lipid Peroxidation ,P22phox ,Protein Kinases ,medicine.drug - Abstract
The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-α and -β₂-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-α and -β2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-β, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-κB activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-α and -β₂-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy.
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- 2012
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24. Modulation of AT-1R/AMPK-MAPK cascade plays crucial role for the pathogenesis of diabetic cardiomyopathy in transgenic type 2 diabetic (Spontaneous Diabetic Torii) rats
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Arun Prasath Lakshmanan, Vivian Soetikno, Rajarajan Amirthalingam Thandavarayan, Ritsuo Takagi, Kenichi Watanabe, Kenji Suzuki, Masaki Nagata, Makoto Kodama, Meilei Harima, and Vijayakumar Sukumaran
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Blood Glucose ,Male ,MAPK/ERK pathway ,medicine.medical_specialty ,Diabetic Cardiomyopathies ,p38 mitogen-activated protein kinases ,Cardiomyopathy ,AMP-Activated Protein Kinases ,MAPK cascade ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Receptor, Angiotensin, Type 1 ,Animals, Genetically Modified ,Rats, Sprague-Dawley ,Renin-Angiotensin System ,Superoxides ,Fibrosis ,Diabetic cardiomyopathy ,Internal medicine ,medicine ,Animals ,Insulin ,Caspase 12 ,Pharmacology ,business.industry ,NADPH Oxidases ,AMPK ,medicine.disease ,Angiotensin II ,Rats ,Endocrinology ,Diabetes Mellitus, Type 2 ,Mitogen-Activated Protein Kinases ,business - Abstract
There are evidences that the activation of AMPK is playing pivotal role in the lipid and glucose metabolism. It has been reported that both the AMPK and angiotensin-II acts as a negative regulator for each protein. It has been well proven that the MAPK cascade could be modulated by the presence of angiotensin-II. Moreover, studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation. Therefore, we speculate and tried to demonstrate that the modulation of AT-R/MAPK pathway through AMPK might play crucial roles for the pathogenesis of diabetic cardiomyopathy, using the transgenic (Spontaneous Diabetic Torii-SDT) rats. We performed Western blot analysis for the measurement of myocardial AT-R, AMPK and MAPK cascades-related protein expressions, p67-phox and caspase-12. In addition, we employed dihydroethidium (DHE), Azan Mallory and hemotoxylin eosin (HE) staining methods to demonstrate the superoxide radical production, fibrosis and hypertrophy, respectively. The protein expressions, such as AT-1R, p-ERK1/2, p67-phox and caspase-12 were found to be significantly increased and conversely, the Ang-(1-7) mas R, Tak1, LKB1 and p-AMPKα1, p-p38 MAPK and p-JNK protein expressions were found to be considerably decreased in the SDT rats, in comparison to the normal rats. The DHE, Azan Mallory and HE stainings also revealed that the SDT rats have more superoxide radical production, fibrosis and hypertrophy, respectively than the normal rats. Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy.
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- 2012
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25. Telmisartan acts through the modulation of ACE-2/ANG 1–7/mas receptor in rats with dilated cardiomyopathy induced by experimental autoimmune myocarditis
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Makoto Kodama, Arun Prasath Lakshmanan, Ken'ichi Yamaguchi, Narasimman Gurusamy, Vijayakumar Sukumaran, Meilei Ma, Kenichi Watanabe, Kenji Suzuki, and Punniyakoti T. Veeraveedu
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Cardiomyopathy, Dilated ,Male ,medicine.medical_specialty ,Myocarditis ,Blotting, Western ,Cardiomyopathy ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,Peptidyl-Dipeptidase A ,Real-Time Polymerase Chain Reaction ,Benzoates ,Proto-Oncogene Mas ,General Biochemistry, Genetics and Molecular Biology ,Nervous System Autoimmune Disease, Experimental ,Receptors, G-Protein-Coupled ,Muscle hypertrophy ,Atrial natriuretic peptide ,Superoxides ,Proto-Oncogene Proteins ,Internal medicine ,Animals ,Medicine ,Telmisartan ,General Pharmacology, Toxicology and Pharmaceutics ,Antihypertensive Agents ,business.industry ,Dilated cardiomyopathy ,General Medicine ,medicine.disease ,Rats ,CTGF ,Disease Models, Animal ,Endocrinology ,Gene Expression Regulation ,Rats, Inbred Lew ,Angiotensin-converting enzyme 2 ,Benzimidazoles ,Angiotensin-Converting Enzyme 2 ,business ,medicine.drug - Abstract
Aim Recent findings have suggested that a therapeutic approach to amplify or stimulate the angiotensin-converting enzyme-2 [ACE-2]-angiotensin 1–7 [ANG 1–7] mas axis could provide protection against the development of cardiovascular diseases. We investigated the cardioprotective effects of telmisartan in rats with dilated cardiomyopathy [DCM] after experimental autoimmune myocarditis [EAM]. Main methods DCM was elicited in Lewis rats by immunization with cardiac myosin, and twenty-eight days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10 mg/kg/day) or vehicle. Key findings Telmisartan treatment effectively suppressed myocardial protein and mRNA expressions of inflammatory markers [CD68, iNOS, NF-kB, interleukin-1β, interferon-γ, monocyte chemotactic protein-1] in comparison to vehicle-treated rats. In contrast, myocardial protein levels of ACE-2 and ANG 1–7 mas receptor were upregulated in the telmisartan-treated group compared with vehicle-treated rats. Telmisartan treatment significantly reduced fibrosis and hypertrophy and their marker molecules [OPN, CTGF, TGF-β1 and collagens I and III and atrial natriuretic peptide and GATA-4, respectively] compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly lowered the protein expressions of NADPH oxidase subunits p47phox, p67phox, and superoxide production when compared with vehicle-treated rats. Telmisartan treatment significantly decreased the expression levels of mitogen-activated protein kinase (MAPK) signaling molecules than with those of vehicle-treated rats. Also, telmisartan treatment significantly improved LV systolic and diastolic function. Significance These results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling through the modulation of ACE-2/ANG 1–7/Mas receptor axis in rats with DCM after EAM.
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- 2012
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26. Modulation of endoplasmic reticulum stress and cardiomyocyte apoptosis by mulberry leaf diet in experimental autoimmune myocarditis rats
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Arun Prasath Lakshmanan, Vivian Soetikno, Wawaimuli Arozal, Vijayasree V. Giridharan, Flori R. Sari, Kenichi Watanabe, Makoto Kodama, Kenji Suzuki, Somasundaram Arumugam, Meilei Ma, Rajarajan Amirthalingam Thandavarayan, Vijayakumar Sukumaran, and Punniyakoti T. Veeraveedu
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Cardiac function curve ,medicine.medical_specialty ,Cardiac fibrosis ,Clinical Biochemistry ,Medicine (miscellaneous) ,Apoptosis ,medicine.disease_cause ,Internal medicine ,medicine ,experimental autoimmune myocarditis ,oxidative stress ,Myocyte ,Protein kinase A ,Nutrition and Dietetics ,biology ,business.industry ,Endoplasmic reticulum ,mulberry leaves ,medicine.disease ,Endocrinology ,Mitogen-activated protein kinase ,endoplasmic reticulum stress ,biology.protein ,Original Article ,business ,Oxidative stress - Abstract
Mulberry is commonly used as silkworm diet and an alternative medicine in Japan and China, has recently reported to contain many antioxidative flavanoid compounds and having the free radical scavenging effects. Antioxidants reduce cardiac oxidative stress and attenuate cardiac dysfunction in animals with pacing-induced congestive heart failure. Hence we investigated the cardioprotective effect of mulberry leaf powder in rats with experimental autoimmune myocarditis. Eight-week-old Lewis rats immunized with cardiac myosin were fed with either normal chow or a diet containing 5% mulberry leaf powder and were examined on day 21. ML significantly decreased oxidative stress, myocyte apoptosis, cellular infiltration, cardiac fibrosis, mast cell density, myocardial levels of sarco/endo-plasmic reticulum Ca(2+) ATPase2, p22(phox), receptor for advanced glycation end products, phospho-p38 mitogen activated protein kinase, phospho-c-Jun NH(2)-terminal protein kinase, glucose regulated protein78, caspase12 and osteopontin levels in EAM rats. These results may suggest that mulberry diet can preserve the cardiac function in experimental autoimmune myocarditis by modulating oxidative stress induced MAPK activation and further afford protection against endoplasmic reticulum stress mediated apoptosis.
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- 2012
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27. Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium
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Kenichi Watanabe, Kenji Suzuki, Vijayakumar Sukumaran, Tomoyuki Kawase, Yusuke Kawauchi, Masaki Nagata, Hitoshi Asakura, Hiroyuki Yoneyama, Hana Yamaguchi, Takayoshi Nishino, Hiroshi Kawachi, and Xiaomei Sun
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Pathology ,medicine.medical_specialty ,biology ,Chemistry ,Vimentin ,General Medicine ,medicine.disease ,Inflammatory bowel disease ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,Cellular infiltration ,Collagen, type I, alpha 1 ,medicine ,biology.protein ,Colitis ,Myofibroblast ,Acute colitis - Abstract
Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin(+), α-smooth muscle actin (α-SMA)(-)) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin(+), α-SMA(+)) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.
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- 2011
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28. Telmisartan ameliorates experimental autoimmune myocarditis associated with inhibition of inflammation and oxidative stress
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Kenichi Watanabe, Kenji Suzuki, Ken'ichi Yamaguchi, Meilei Ma, Narasimman Gurusamy, Yoshifusa Aizawa, Makoto Kodama, Punniyakoti T. Veeraveedu, Varatharajan Rajavel, and Vijayakumar Sukumaran
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Male ,medicine.medical_specialty ,Myocarditis ,medicine.medical_treatment ,Blotting, Western ,Angiotensin-Converting Enzyme Inhibitors ,Enzyme-Linked Immunosorbent Assay ,Inflammation ,medicine.disease_cause ,Benzoates ,Autoimmune Diseases ,Proinflammatory cytokine ,Internal medicine ,medicine ,Animals ,Telmisartan ,Pharmacology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Interleukin ,Endomyocardial Fibrosis ,medicine.disease ,Angiotensin II ,Rats ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,Cytokine ,Rats, Inbred Lew ,Cytokines ,Benzimidazoles ,medicine.symptom ,business ,Oxidative stress ,medicine.drug - Abstract
Excess cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Angiotensin-II has been shown to play a pivotal role in the pathophysiology of various organs, especially the cardiovascular system. Some angiotensin II type 1 receptor antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We investigated whether telmisartan, an angiotensin II type 1 receptor antagonist protects against experimental autoimmune myocarditis by suppression of inflammatory cytokines and oxidative stress. Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with either telmisartan (10 mg/kg/day) or vehicle for 21 days. Age-matched normal rats without immunization were also included in this study. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Increased myocardial mRNA expressions of inflammatory cytokines [interleukin (IL-6), IL-1β, tumor necrosis factor-α and interferon-γ] were also suppressed by telmisartan treatment compared with vehicle-treated rats. Myocardial protein expressions of NADPH oxidase subunits p47phox, Nox-4, and gp91phox, myocardial levels of 8-hydroxydeoxyguanosine and 4-hydroxy-2-nonenal, and myocardial apoptosis were also significantly decreased by telmisartan treatment compared with vehicle-treated rats. Further, telmisartan significantly decreased endoplasmic reticulum stress markers in experimental autoimmune myocarditis rats. These findings suggest that telmisartan protects against experimental autoimmune myocarditis in rats, at least in part by suppressing inflammatory cytokines and oxidative stress; however, further investigations are needed before clinical use.
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- 2011
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29. Curcumin Ameliorates Cardiac Inflammation in Rats with Autoimmune Myocarditis
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Punniyakoti T. Veeraveedu, Vijayakumar Sukumaran, Yoshifusa Aizawa, Rajarajan Amirthalingam Thandavarayan, Kenichi Watanabe, Sayaka Mito, Kenji Suzuki, Meilei Harima, and Makoto Kodama
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Male ,Pathology ,medicine.medical_specialty ,Curcumin ,Myocarditis ,H&E stain ,Pharmaceutical Science ,Enzyme-Linked Immunosorbent Assay ,Inflammation ,Traditional Chinese medicine ,Pharmacology ,Autoimmune Diseases ,chemistry.chemical_compound ,Animals ,Medicine ,RNA, Messenger ,Curcuma ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,NF-kappa B ,Interleukin ,General Medicine ,medicine.disease ,biology.organism_classification ,GATA4 Transcription Factor ,Rats ,chemistry ,Rats, Inbred Lew ,Cytokines ,Tumor necrosis factor alpha ,medicine.symptom ,business - Abstract
Curcumin is a natural polyphenolic compound abundant in the rhizome of the perennial herb turmeric, Curcuma longa. It is commonly used as a dietary spice and coloring agent in cooking, and is used anecdotally as an herb in traditional Indian and Chinese medicine. It has been reported that curcumin has the potential to protect against cardiac inflammation through suppression of GATA-4 and nuclear factor-κB (NF-κB); however, no study to date has addressed the effect of curcumin on experimental autoimmune myocarditis (EAM) in rats. In this study, 8-week-old male Lewis rats were immunized with cardiac myosin to induce EAM. They were then divided randomly into a treatment or vehicle group and orally administrated curcumin (50 mg/kg/d) or 1% gum arabic, respectively, for 3 weeks after myosin injection. We performed hemodynamic, echocardiographic, hematoxylin and eosin staining, mast cell staining and Western blotting studies to evaluate the protective effect of curcumin in the acute phase of EAM. Cardiac functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by curcumin treatment. Furthermore, curcumin reduced the heart weight-to-body weight ratio, area of inflammatory lesions and the myocardial protein level of NF-κB, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and GATA-4. Our results indicate that curcumin has the potential to protect against cardiac inflammation through suppression of IL-1β, TNF-α, GATA-4 and NF-κB expresses, and may provide a novel therapeutic strategy for autoimmune myocarditis.
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- 2011
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30. Beneficial effects of olmesartan, an angiotensin II receptor type 1 antagonist, in rats with dilated cardiomyopathy
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Ken'ichi Yamaguchi, Punniyakoti T. Veeraveedu, Kenichi Watanabe, Yoshifusa Aizawa, Kenji Suzuki, Makoto Kodama, Meilei Ma, Narasimman Gurusamy, Rajarajan Amirthalingam Thandavarayan, and Vijayakumar Sukumaran
- Subjects
Cardiomyopathy, Dilated ,Male ,Cardiac function curve ,medicine.medical_specialty ,Cardiac fibrosis ,Interleukin-1beta ,Cardiomyopathy ,Tetrazoles ,Myosins ,General Biochemistry, Genetics and Molecular Biology ,Internal medicine ,Idiopathic dilated cardiomyopathy ,medicine ,Animals ,RNA, Messenger ,Ventricular remodeling ,Chemokine CCL2 ,Angiotensin II receptor type 1 ,Ventricular Remodeling ,Interleukin-6 ,business.industry ,Angiotensin II ,Myocardium ,Imidazoles ,medicine.disease ,Rats ,Myocarditis ,Endocrinology ,Matrix Metalloproteinase 9 ,Rats, Inbred Lew ,cardiovascular system ,Matrix Metalloproteinase 2 ,business ,Olmesartan ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Favorable effects of angiotensin II type 1 receptor blockers on patients with ischemic or idiopathic dilated cardiomyopathy (DCM) have already been suggested by several human trials, but their effects on DCM remain unknown. Hence, we investigated the effect of olmesartan on myocardial remodeling in a rat model in which myosin-induced experimental autoimmune myocarditis (EAM) might develop into DCM. EAM was elicited in Lewis rats by immunization with cardiac myosin, and 28 d after immunization, the surviving Lewis rats were divided into two groups and treated with either olmesartan (10 mg/kg/d) or vehicle. Age-matched normal rats without immunizations were also used. After four weeks of treatment, we investigated the effects of olmesartan on cardiac function, inflammatory cytokines and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic analyses were significantly improved by the treatment with olmesartan compared with those of vehicle-treated rats. Olmesartan significantly reduced cardiac fibrosis as well as hypertrophy and its molecular markers (left ventricular [LV] mRNA expressions of transforming growth factor beta1, collagen-I and -III, and atrial natriuretic peptide) compared with those of vehicle-treated rats. Increased myocardial mRNA expressions of proinflammatory cytokines (interleukin [IL]-6, IL-1β), monocyte chemoattractant protein-1 and matrix metalloproteinases (MMP-2 and -9) were also suppressed by the treatment with olmesartan in rats with DCM. Further, the plasma level of angiotensin II was significantly increased in olmesartan-treated rats. These findings demonstrate that olmesartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with DCM after EAM.
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- 2010
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31. Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats
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Makoto Kodama, Yoshifusa Aizawa, Meilei Ma, Rajarajan Amirthalingam Thandavarayan, Wawaimuli Arozal, Punniyakoti T. Veeraveedu, Vijayakumar Sukumaran, Kenichi Watanabe, and Kenji Suzuki
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Male ,medicine.medical_specialty ,Heart Diseases ,Anthracycline ,Adrenergic beta-Antagonists ,Carbazoles ,Renal function ,Antineoplastic Agents ,Apoptosis ,Kidney ,Kidney Function Tests ,Toxicology ,Nephrotoxicity ,Propanolamines ,Rats, Sprague-Dawley ,Internal medicine ,medicine ,Animals ,Carvedilol ,health care economics and organizations ,Cardiotoxicity ,Antibiotics, Antineoplastic ,business.industry ,Myocardium ,Daunorubicin ,Hemodynamics ,Kidney metabolism ,Heart ,medicine.disease ,Rats ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,Creatinine ,Matrix Metalloproteinase 2 ,business ,Kidney disease ,medicine.drug - Abstract
Daunorubicin (DNR) is one of the anthracycline anti-tumor agents widely used in the treatment of acute myeloid leukemia. However, the clinical use of DNR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of carvedilol, a nonselective beta-blocker against DNR-induced cardiotoxicity and nephrotoxicity. Rats were treated with a cumulative dose of 9 mg/kg body weight DNR (i.v.). Carvedilol was administered orally every day for 6 weeks. DNR rats showed cardiac and nephrotoxicities as evidenced by worsening cardiac and kidney functions, which were evaluated by hemodynamic and echocardiographic studies, and by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdeyde level and the total level of glutathione peroxidase activity in both heart and kidney tissues. These changes were reversed by treatment with carvedilol, which resulted in significant improvement in the cardio-renal function. Furthermore, carvedilol down-regulated matrix metalloproteinase-2 expression in the heart, increased nephrin expression in the kidney, and attenuated the increased protein expression of NADPH oxidase subunits in heart and kidney. Moreover, carvedilol reduced myocardial and renal apoptosis and improved the histopathological changes in heart and kidney induced by DNR. In conclusion, the present study demonstrated a beneficial effect of carvedilol treatment in the prevention of DNR-induced cardiotoxicity and nephrotoxicity by reversing the oxidative stress and apoptosis.
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- 2010
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32. Telmisartan, an angiotensin-II receptor blocker ameliorates cardiac remodeling in rats with dilated cardiomyopathy
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Narasimman Gurusamy, Makoto Kodama, Rajarajan Amirthalingam Thandavarayan, Meilei Ma, Punniyakoti T. Veeraveedu, Kenichi Watanabe, Ken'ichi Yamaguchi, Kenji Suzuki, Yoshifusa Aizawa, and Vijayakumar Sukumaran
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Cardiomyopathy, Dilated ,Male ,Cardiac function curve ,medicine.medical_specialty ,Angiotensin receptor ,Physiology ,Cardiac fibrosis ,Cardiomyopathy ,Benzoates ,Autoimmune Diseases ,Proinflammatory cytokine ,Atrial natriuretic peptide ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Telmisartan ,cardiovascular diseases ,Heart Failure ,Ventricular Remodeling ,business.industry ,Myocardium ,medicine.disease ,Fibrosis ,Rats ,Myocarditis ,Endocrinology ,Matrix Metalloproteinase 9 ,Rats, Inbred Lew ,Heart failure ,Chronic Disease ,cardiovascular system ,Cardiology ,Cytokines ,Matrix Metalloproteinase 2 ,Benzimidazoles ,Cardiology and Cardiovascular Medicine ,business ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Multiple trials over the past several years have examined indications for angiotensin receptor blockers (ARBs) in the treatment of left ventricular (LV) dysfunction, both acutely after myocardial infarction and in chronic heart failure (CHF). However, the effects of telmisartan, an ARB in rats with CHF after experimental autoimmune myocarditis (EAM) have not yet been analyzed. CHF was elicited in Lewis rats by immunization with cardiac myosin, and 28 days after immunization, the surviving Lewis rats were divided into two groups and treated with either telmisartan (10 mg kg(-1) day(-1)) or vehicle. After 4 weeks of treatment, we analyzed the effects of telmisartan on cardiac function, proinflammatory cytokines and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by telmisartan treatment in rats with CHF compared with those of vehicle-treated rats with CHF. Telmisartan significantly reduced levels of cardiac fibrosis, hypertrophy and its marker molecules (LV mRNA expressions of transforming growth factor beta 1, collagen I and III, and atrial natriuretic peptide), and peroxisome proliferator-activated receptor--gamma protein expression compared with those of vehicle-treated rats. CHF-induced increases in myocardial mRNA expressions of proinflammatory cytokines, (interleukin (IL)-6, IL-1beta), monocyte chemoattractant protein-1 and matrix metalloproteinases (MMP-2 and -9) were also suppressed by the treatment with telmisartan. Moreover, the plasma level of angiotensin-II was significantly elevated in telmisartan-treated rats. Our results indicate that telmisartan treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.
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- 2010
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33. Role of Differential Signaling Pathways and Oxidative Stress in Diabetic Cardiomyopathy
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Wawaimuli Arozal, Yoshifusa Aizawa, Meilei Harima, Flori R. Sari, Arun Prasath Laksmanan, Makoto Kodama, Narasimman Gurusamy, Sayaka Mito, Rajarajan Amirthalingam Thandavarayan, Kenichi Watanabe, Vivian Soetikno, Vijayakumar Sukumaran, and Punniyakoti T. Veeraveedu
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medicine.medical_specialty ,business.industry ,Cardiomyopathy ,apoptosis ,General Medicine ,medicine.disease ,medicine.disease_cause ,Article ,Pathogenesis ,Coronary artery disease ,Endocrinology ,Diabetes mellitus ,hypertrophy ,Internal medicine ,Heart failure ,Diabetic cardiomyopathy ,medicine ,oxidative stress ,Endothelial dysfunction ,Cardiology and Cardiovascular Medicine ,business ,cardiomyopathy ,Oxidative stress - Abstract
Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.
- Published
- 2010
34. Uric Acid is Positively Associated with Metabolic Syndrome but Negatively Associated with Diabetes in Japanese Men
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Ryu Kawai, Kenichi Watanabe, Vijayakumar Sukumaran, and Eiji Oda
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Adult ,Male ,medicine.medical_specialty ,Cross-sectional study ,Physiology ,Uric acid blood ,Fasting glucose ,chemistry.chemical_compound ,Negatively associated ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Metabolic Syndrome ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Uric Acid ,Cross-Sectional Studies ,Endocrinology ,Quartile ,chemistry ,Uric acid ,Female ,Metabolic syndrome ,business ,Biomarkers - Abstract
Background The relationships between uric acid and metabolic syndrome (MetS) and diabetes, as well as the gender differences in these relationships are controversial. Methods Medical check-up data from 2,449 Japanese men and 1,448 Japanese women were examined. The prevalence of MetS and diabetes was calculated by the quartiles of serum levels of uric acid. Correlation coefficients between uric acid and MetS-related risk factors were calculated and compared between men and women. Results The prevalence of MetS in the 3rd quartile (Q3) of uric acid was significantly higher than that in the 1st (lowest) quartile (Q1) and the prevalence of MetS in the 4th quartile (Q4) was significantly higher than that in Q1, the 2nd quartile (Q2), and Q3 in men. The prevalence of MetS in Q4 was significantly higher than that in Q1, Q2, and Q3 in women. The prevalence of diabetes in Q3 was significantly lower than that in Q1 and the prevalence of diabetes in Q4 was significantly lower than that in Q1 and Q2 in men. The prevalence of diabetes was not significantly different among the quartiles of uric acid in women. The age-adjusted correlation coefficient between uric acid and fasting glucose was not significant in men. Conclusion Uric acid is positively associated with metabolic syndrome but negatively associated with diabetes in Japanese men.
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- 2009
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35. Prevalence of Metabolic Syndrome Increases with the Increase in Blood Levels of Gamma Glutamyltransferase and Alanine Aminotransferase in Japanese Men and Women
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Kenichi Watanabe, Ryu Kawai, Eiji Oda, and Vijayakumar Sukumaran
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Adult ,Male ,medicine.medical_specialty ,Cross-sectional study ,digestive system ,Asian People ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Prevalence ,Internal Medicine ,medicine ,Humans ,Alanine aminotransferase ,Gamma-glutamyltransferase ,Risk factor ,Metabolic Syndrome ,biology ,business.industry ,Fatty liver ,Alanine Transaminase ,gamma-Glutamyltransferase ,General Medicine ,Middle Aged ,medicine.disease ,digestive system diseases ,Cross-Sectional Studies ,Endocrinology ,Quartile ,biology.protein ,Female ,Metabolic syndrome ,business - Abstract
Background Gamma glutamyltransferase (GGT) or alanine aminotransferase (ALT) is reported to be an independent risk factor of diabetes and cardiovascular disease and proposed as a component of metabolic syndrome (MS). However, there are few studies examining the direct association between MS and GGT or ALT in Japanese men and women. Methods Direct associations between GGT or ALT and MS defined by revised NCEP criteria for Japanese and between GGT or ALT and Japanese MS (JMS) defined by the Examination Committee for the Criteria of Metabolic Syndrome were examined using medical check-up data from 1,880 men and 1,079 women. Results The prevalence of MS and JMS was significantly higher in subjects with the highest quartile of GGT or ALT than the subjects with the lowest quartile of GGT or ALT (p
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- 2009
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36. LDL Cholesterol is More Strongly Associated with Metabolic Syndrome in Japanese Women Than in Men
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Vijayakumar Sukumaran, Kenichi Watanabe, Eiji Oda, and Ryu Kawai
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Adult ,Male ,medicine.medical_specialty ,Blood Pressure ,chemistry.chemical_compound ,Asian People ,Japan ,Risk Factors ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Gamma-glutamyltransferase ,Aged ,Glycated Hemoglobin ,Metabolic Syndrome ,Sex Characteristics ,biology ,Receiver operating characteristic ,business.industry ,Cholesterol ,Cholesterol, LDL ,gamma-Glutamyltransferase ,General Medicine ,Middle Aged ,medicine.disease ,Confidence interval ,Blood pressure ,Endocrinology ,chemistry ,Cardiovascular Diseases ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Hemoglobin ,Metabolic syndrome ,business ,Sex characteristics - Abstract
Objective LDL cholesterol is not usually considered as a component of metabolic syndrome (MetS) but rather it is associated with MetS components. Methods Data from 2,449 men and 1,448 women were examined using receiver operating characteristic (ROC) curve for diagnosing MetS and correlation coefficients. Results Blood levels of LDL cholesterol increased more steeply in women than in men as the number of MetS components increased. The area under ROC curve (AUC) and its 95% confidence interval (CI) of LDL cholesterol for diagnosing MetS were 0.57 and 0.53-0.60 in men and 0.66 and 0.61-0.71 in women. The optimal cut-off point (sensitivity; specificity) of LDL cholesterol was 127 mg/dL (0.50; 0.60) in men and 125 mg/dL (0.64; 0.61) in women. Correlations between LDL cholesterol and systolic blood pressure, diastolic blood pressure, gamma glutamyltransferase, and hemoglobin A1c were stronger in women than in men even after adjustment for age. The correlation between LDL cholesterol and blood pressure was significant in women, but not in men, even after adjusting for age. Conclusion LDL cholesterol was more strongly associated with MetS in Japanese women than in men. The correlation between LDL cholesterol and blood pressure was significant in women, but not in men.
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- 2009
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37. Sox9 Controls Self-Renewal of Oncogene Targeted Cells and Links Tumor Initiation and Invasion
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Véronique Del Marmol, François Fuks, Cédric Blanpain, Khalil Kass Youssef, Christopher J. Guérin, Saskia Lippens, Adriana Sánchez-Danés, Jean-Christophe Marine, Benjamin Delatte, Jean-Christophe Larsimont, Mélanie Liagre, Matthieu Defrance, Pieter Baatsen, Jean-Marie Vanderwinden, and Vijayakumar Sukumaran
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Male ,endocrine system ,animal structures ,Skin Neoplasms ,Carcinogenesis ,Mice, Transgenic ,Tumor initiation ,Biology ,medicine.disease_cause ,Models, Biological ,Receptors, G-Protein-Coupled ,Extracellular matrix ,Mice ,stomatognathic system ,medicine ,Genetics ,Cell Adhesion ,Animals ,Humans ,Hedgehog Proteins ,Neoplasm Invasiveness ,Cell Self Renewal ,Transcription factor ,Hedgehog ,Mice, Knockout ,Oncogene ,Wnt signaling pathway ,SOX9 Transcription Factor ,Cell Biology ,Oncogenes ,Smoothened Receptor ,Hedgehog signaling pathway ,Cell biology ,Extracellular Matrix ,Actin Cytoskeleton ,Cell Transformation, Neoplastic ,Carcinoma, Basal Cell ,embryonic structures ,Mutation ,Neoplastic Stem Cells ,Molecular Medicine ,Female ,Gene Deletion ,Signal Transduction - Abstract
SummarySox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells. Transcriptional profiling of oncogene-expressing cells with Sox9 deletion, combined with in vivo ChIP sequencing, uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix deposition, and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that link tumor initiation and invasion.
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- 2014
38. Role of Protein Kinase C-MAPK, Oxidative Stress and Inflammation Pathways in Diabetic Nephropathy
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Kenichi Watanabe, Kenji Suzuki, Arun Prasath Lakshamanan, Rajarajan A. Th, Makoto Kodama, avarayan, Ritsuo Takagi, Vivian Soetikno, Hiroshi Kawachi, Meilei Harima, Masaki Nagata, Vijayakumar Sukumaran, Flori R. Sari, and Somasundaram Arumugam
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medicine.medical_specialty ,business.industry ,Inflammation ,medicine.disease_cause ,medicine.disease ,Protein kinase C signaling ,Diabetic nephropathy ,Endocrinology ,Internal medicine ,Medicine ,ASK1 ,Signal transduction ,medicine.symptom ,business ,Oxidative stress ,Protein kinase C ,Diacylglycerol kinase - Abstract
Diabetic nephropathy is the most common cause of end-stage renal disease. It is assumed that hyperglycemia is one of the major systemic risk factors for diabetic complications. Numerous hypotheses exist to enlighten the adverse effect of hyperglycemia. One of these hypotheses is the activation of the calcium- and phospholipid-dependent protein kinase C signaling pathway by hyperglycemia which subsequently mediates cellular response and affects gene expression and protein function to cause cellular dysfunction and damage. It is well known that the intracellular protein kinase C activation is achieved by the elevated diacylglycerol levels in vascular tissues as well as in nonvascular tissues. Besides diacylglycerol, oxidative stress has also been reported to induce prolonged activation of protein kinase C within cells through the reactive oxygen species. Activation of protein kinase C and oxidative stress have been associated with vascular alterations such as increases in permeability of endothelial cells, extracellular matrix synthesis, cell growth and apoptosis, angiogenesis, and cytokines activation and inhibition. These derangements in vascular cell homeostasis caused by the activation protein kinase C as well as oxidative stress are connected to the occurrence of pathologies affecting large vessel and small vessel complications. Accumulating evidences have also shown that the inflammation process is an essential pathogenetic mechanism in diabetic nephropathy. Therefore, modulation of this process is an important target for both metabolic and hemodynamic derangements in diabetic nephropathy. In this review, we will discusses the role of protein kinase C, oxidative stress and inflammation process and the signaling pathway in the pathogenesis of diabetic nephropathy.
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- 2012
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39. Curcumin decreases renal triglyceride accumulation through AMPK-SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats
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Meilei Harima, Kenichi Watanabe, Kenji Suzuki, Arun Prasath Lakshmanan, Vivian Soetikno, Flori R. Sari, Hiroshi Kawachi, and Vijayakumar Sukumaran
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Male ,medicine.medical_specialty ,Curcumin ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,AMP-Activated Protein Kinases ,Kidney ,Biochemistry ,Perilipin-2 ,Streptozocin ,Diabetes Mellitus, Experimental ,Nephrin ,Diabetic nephropathy ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Transforming Growth Factor beta ,Internal medicine ,medicine ,Animals ,Diabetic Nephropathies ,Phosphorylation ,Molecular Biology ,Triglycerides ,Extracellular Matrix Proteins ,Nutrition and Dietetics ,biology ,Triglyceride ,Chemistry ,Vascular Endothelial Growth Factors ,AMPK ,Membrane Proteins ,Streptozotocin ,medicine.disease ,Rats ,Fatty acid synthase ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,Fatty Acid Synthases ,Sterol Regulatory Element Binding Protein 1 ,medicine.drug ,Acetyl-CoA Carboxylase ,Signal Transduction - Abstract
Diabetic kidney disease has been associated with the presence of lipid deposits. We assumed that curcumin, a polyphenol, would attenuate the tissue dyslipidemic condition through activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppression of sterol regulatory element-binding protein (SREBP)-1c in the kidney and would prevent renal progression in experimental type 1 diabetic rats. Diabetes was induced with streptozotocin (STZ) (55 mg/kg) by intraperitoneal injection in male Sprague–Dawley rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic and diabetic treated with curcumin (100 mg/kg/day) by gavage for 8 weeks. We found that curcumin decreased plasma triglyceride and the amount of renal triglyceride significantly. Furthermore, treatment of diabetic rats with curcumin increased the phosphorylation of AMPK and prevented the increased renal expression of SREBP-1c and, as a result, decreased the expression of acetyl CoA carboxylase and fatty acid synthase as well as adipose differentiation-related protein, a marker of cytoplasmic droplets. We also demonstrate that curcumin significantly suppressed the increased expression of transforming growth factor β, vascular endothelial growth factor and extracellular matrix proteins such as type IV collagen and fibronectin. In addition, curcumin treatment increased nephrin expression to near-normal levels in diabetic rats. These results demonstrated that curcumin protects against the development of diabetic nephropathy through the AMPK–SREBP pathway and the reduction of renal triglyceride accumulation which could be a possible mechanism by which curcumin preserves renal function in diabetes.
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- 2011
40. Olmesartan attenuates the development of heart failure after experimental autoimmune myocarditis in rats through the modulation of ANG 1-7 mas receptor
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Masaki Nagata, Ken'ichi Yamaguchi, Kenichi Watanabe, Kenji Suzuki, Ritsuo Takagi, Makoto Kodama, Narasimman Gurusamy, Punniyakoti T. Veeraveedu, Arun Prasath Lakshmanan, Vijayakumar Sukumaran, and Meilei Ma
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MAPK/ERK pathway ,medicine.medical_specialty ,Cardiotonic Agents ,Tetrazoles ,Apoptosis ,Peptidyl-Dipeptidase A ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,Receptor, Angiotensin, Type 1 ,Autoimmune Diseases ,Phosphatidylinositol 3-Kinases ,Endocrinology ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,RNA, Messenger ,Protein kinase A ,Receptor ,Molecular Biology ,Heart Failure ,Inflammation ,NADPH oxidase ,Membrane Glycoproteins ,biology ,Chemistry ,Imidazoles ,JNK Mitogen-Activated Protein Kinases ,NADPH Oxidases ,Receptors, Interleukin-1 ,Endoplasmic Reticulum Stress ,Phosphoproteins ,Angiotensin II ,Peptide Fragments ,Rats ,Myocarditis ,Oxidative Stress ,NADPH Oxidase 4 ,Rats, Inbred Lew ,Angiotensin-converting enzyme 2 ,biology.protein ,Angiotensin-Converting Enzyme 2 ,Angiotensin I ,Olmesartan ,Angiotensin II Type 1 Receptor Blockers ,Proto-Oncogene Proteins c-akt ,medicine.drug - Abstract
Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor.
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- 2011
41. Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice
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Rajarajan Amirthalingam Thandavarayan, Harima Meilei, Vijayakumar Sukumaran, Flori R. Sari, Kenichi Watanabe, Vijayasree V. Giridharan, Kenji Suzuki, Somasundaram Arumugam, Arun Prasath Lakshmanan, Vivian Soetikno, and Makoto Kodama
- Subjects
MAPK/ERK pathway ,Male ,medicine.medical_specialty ,MAP Kinase Signaling System ,Gene Expression ,Tetrazoles ,Apoptosis ,Peptidyl-Dipeptidase A ,Protein Serine-Threonine Kinases ,Kidney ,Biochemistry ,Proto-Oncogene Mas ,p38 Mitogen-Activated Protein Kinases ,Receptor, Angiotensin, Type 1 ,Diabetes Mellitus, Experimental ,Receptors, G-Protein-Coupled ,Diabetic nephropathy ,Mice ,Endocrinology ,Downregulation and upregulation ,Internal medicine ,Diabetes mellitus ,Proto-Oncogene Proteins ,medicine ,Renal fibrosis ,Animals ,Diabetic Nephropathies ,Phosphorylation ,Molecular Biology ,business.industry ,Imidazoles ,Intracellular Signaling Peptides and Proteins ,medicine.disease ,Streptozotocin ,Enzyme Activation ,Mice, Inbred C57BL ,Oxidative Stress ,Angiotensin-Converting Enzyme 2 ,Olmesartan ,business ,Angiotensin II Type 1 Receptor Blockers ,Kidney disease ,medicine.drug - Abstract
There is increasing evidence that angiotensin (Ang)-II plays an unprecedented role in diabetic complications. It could also be an important therapeutic target for ameliorating various diseases, especially diabetic nephropathy (DN). We therefore studied the beneficial effects of olmesartan, an Ang-II type 1 receptor (AT-1R) blocker in streptozotocin (150 mg/kg, BW)-induced diabetic kidney disease in mice. The diabetic kidney mice displayed upregulated protein expression levels of AT-1R, AT-2R, ERK-1/2, p-p38 MAPK, p-MAPKAPK-2, ET-1, p-JNK, p-c-Jun, TGF-β1, and gp91-phox, and all of these effects were expectedly downregulated by an olmesartan treatment. Also, immunohistochemical analysis, and Azan-Mallory and HE staining were performed to examine the expression of collagen-III and fibronectin, renal fibrosis, and hypertrophy, respectively. Furthermore, olmesartan treatment significantly abrogated the downregulation of ACE-2 and Ang-(1–7) mas R protein expression in diabetic kidney mice. Considering all these findings together, the AT-1R/MAPK pathway might be a potential therapeutic target in diabetes kidney disease, and olmesartan treatment could have beneficial effects on DN by modulating the AT-1R/MAPK pathway.
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- 2011
42. Analysis of intestinal fibrosis in chronic colitis in mice induced by dextran sulfate sodium
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Kenji, Suzuki, Xiaomei, Sun, Masaki, Nagata, Tomoyuki, Kawase, Hana, Yamaguchi, Vijayakumar, Sukumaran, Yusuke, Kawauchi, Hiroshi, Kawachi, Takayoshi, Nishino, Kenichi, Watanabe, Hiroyuki, Yoneyama, and Hitoshi, Asakura
- Subjects
Reverse Transcriptase Polymerase Chain Reaction ,Blotting, Western ,Dextran Sulfate ,Fluorescent Antibody Technique ,Fibroblasts ,Colitis ,Fibrosis ,Extracellular Matrix ,Mice, Inbred C57BL ,Mice ,Animals ,Cytokines ,Female ,Collagen ,Intestinal Mucosa ,Myofibroblasts - Abstract
Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin(+), α-smooth muscle actin (α-SMA)(-)) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin(+), α-SMA(+)) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.
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- 2011
43. Regulation of inflammation and myocardial fibrosis in experimental autoimmune myocarditis
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Kenichi Watanabe, Kenji Suzuki, Meilei Ma, Varatharajan Rajavel, Somasundaram Arumugam, Narasimman Gurusamy, Vijayakumar Sukumaran, Punniyakoti T. Veeraveedu, Rajarajan Amirthalingam Thandavarayan, Arun Prasath Lakshmanan, Vivian Soetikno, Flori R. Sari, and Wawaimuli Arozal
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Cellular immunity ,Pathology ,medicine.medical_specialty ,Myocarditis ,Cardiac fibrosis ,Immunology ,Angiotensin-Converting Enzyme Inhibitors ,Autoantigens ,Proinflammatory cytokine ,Autoimmune Diseases ,Angiotensin Receptor Antagonists ,Mice ,Fibrosis ,medicine ,Immunology and Allergy ,Animals ,Humans ,cardiovascular diseases ,Pharmacology ,Inflammation ,business.industry ,Myocardium ,Dilated cardiomyopathy ,General Medicine ,medicine.disease ,Rats ,Organ Specificity ,Heart failure ,Models, Animal ,Myocardial fibrosis ,business ,Cardiac Myosins - Abstract
Autoimmune responses and inflammation are involved in the pathogenesis of many cardiovascular diseases. There is compelling evidence that inflammatory mechanisms may contribute to progressive heart failure. Thus, myocardial infiltration of lymphocytes and mononuclear cells, increased expression of pro-inflammatory chemokines and cytokines and circulating autoantibodies are frequently observed in myocarditis and dilated cardiomyopathy (DCM). Experimental autoimmune myocarditis (EAM) in rodents may be elicited by immunization of cardiac myosin and EAM in rats mimics human fulminant myocarditis in the acute phase and human DCM in the chronic phase. Our animal model, EAM was demonstrated to progress into the clinicopathological state similar to DCM in the chronic phase, and was found to be characterized by the enlargement of the heart, dilatation of ventricles, diffuse and extensive myocardial fibrosis, besides being a cellular immunity and inflammation mediated disease. Severity of myocarditis was characterized by increased inflammation, cardiac fibrosis and decreased myocardial performance in rats with DCM. Pharmacological interventions such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) significantly attenuated the myosin-induced inflammation and cardiac fibrosis and thereby improving myocardial function in rats with DCM. A growing body of evidence shows that ACEI and ARBs contribute to the pharmaceutical management of patients with heart failure mediated by immune and inflammatory response. The purpose of this review is to emphasize the role of inflammation and myocardial fibrosis in rats with DCM after EAM and study the effects of pharmacological interventions such as ACEI, ARBs in the treatment of heart failure through the suppression of inflammatory cytokines and fibrosis.
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- 2011
44. Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis
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Arun Prasath Lakshmanan, Ken'ichi Yamaguchi, Punniyakoti T. Veeraveedu, Narasimman Gurusamy, Meilei Ma, Kenichi Watanabe, Kenji Suzuki, Vijayakumar Sukumaran, and Makoto Kodama
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MAPK/ERK pathway ,Male ,Apoptosis ,Endoplasmic Reticulum ,telmisartan ,Applied Microbiology and Biotechnology ,Benzoates ,Experimental autoimmune myocarditis ,Superoxides ,oxidative stress ,NADPH oxidase ,biology ,Myocarditis ,Angiotensin-converting enzyme 2 ,endoplasmic reticulum stress ,Cytokines ,Angiotensin-Converting Enzyme 2 ,medicine.symptom ,Mitogen-Activated Protein Kinases ,medicine.drug ,Signal Transduction ,Research Paper ,medicine.medical_specialty ,Inflammation ,Peptidyl-Dipeptidase A ,Protective Agents ,Proinflammatory cytokine ,Internal medicine ,medicine ,Animals ,Protein kinase A ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Heart Failure ,NADPH Oxidases ,Cell Biology ,Angiotensin II ,Peptide Fragments ,signaling pathways ,Rats ,Disease Models, Animal ,Protein Subunits ,Endocrinology ,inflammation ,biology.protein ,Benzimidazoles ,Telmisartan ,Angiotensin I ,Angiotensin II Type 1 Receptor Blockers ,Biomarkers ,Developmental Biology - Abstract
Angiotensin-converting enzyme-2 (ACE-2) is a homolog of ACE that preferentially forms angiotensin-(ANG)-1-7 from angiotensin II (ANG II). We investigated the cardioprotective effects of telmisartan, a well-known angiotensin receptor blockers (ARBs) against experimental autoimmune myocarditis (EAM). EAM was induced in Lewis rats by immunization with porcine cardiac myosin. The rats were divided into two groups and treated with telmisartan (10 mg/kg/day) or vehicle for 21 days. Myocardial functional parameters were significantly improved by treatment with telmisartan compared with vehicle-treated rats. Telmisartan lowered myocardial protein expressions of NADPH oxidase subunits 3-nitrotyrosine, p47phox, p67 phox, Nox-4 and superoxide production significantly than vehicle-treated rats. In contrast myocardial protein levels of ACE-2, ANG 1-7 mas receptor were upregulated in the telmisartan treated group compared with those of vehicle-treated rats. The myocardial protein expression levels of tumor necrosis factor receptor (TNFR)-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and glucose-regulated protein (GRP) 78 were decreased in the telmisartan treated rats compared with those of vehicle-treated rats. In addition, telmisartan treatment significantly decreased the protein expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho (MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, telmisartan significantly decreased the production of proinflammatory cytokines, myocardial apoptotic markers and caspase-3 positive cells compared with those of vehicle-treated rats. Therefore, we suggest that telmisartan was beneficial protection against heart failure in rats, at least in part by suppressing inflammation, oxidative stress, ER stress as well as signaling pathways through the modulation of ACE2/ANG1-7/Mas receptor axis.
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- 2011
45. Curcumin attenuates diabetic nephropathy by inhibiting PKC-α and PKC-β1 activity in streptozotocin-induced type I diabetic rats
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Kenichi Watanabe, Arun Prasath Lakshmanan, Vivian Soetikno, Kenji Suzuki, Punniyakoti T. Veeraveedu, Meilei Harima, Vijayakumar Sukumaran, Rajarajan Amirthalingam Thandavarayan, Wawaimuli Arozal, Flori R. Sari, and Somasundaram Arumugam
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Male ,medicine.medical_specialty ,Curcumin ,Protein Kinase C-alpha ,MAP Kinase Signaling System ,medicine.medical_treatment ,Intraperitoneal injection ,Kidney ,Antioxidants ,Streptozocin ,Diabetic nephropathy ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Random Allocation ,Internal medicine ,Diabetes mellitus ,Protein Kinase C beta ,medicine ,Animals ,Diabetic Nephropathies ,RNA, Messenger ,Protein Kinase Inhibitors ,Protein kinase C ,Protein Kinase C ,Extracellular Matrix Proteins ,Kidney metabolism ,NADPH Oxidases ,medicine.disease ,Streptozotocin ,Phosphoproteins ,Rats ,CTGF ,Isoenzymes ,Oxidative Stress ,Endocrinology ,Diabetes Mellitus, Type 1 ,chemistry ,Gene Expression Regulation ,NADPH Oxidase 4 ,Food Science ,Biotechnology ,medicine.drug - Abstract
Scope: We hypothesized that curcumin, a potent anti-oxidant, might be beneficial in ameliorating the development of diabetic nephropathy through inhibition of PKC-α and PKC-β1 activity-ERK1/2 pathway. Methods and results: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) in rats. Three weeks after STZ injection, rats were divided into three groups, namely, normal, diabetic and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 wk. At 11 wk after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood urea nitrogen (BUN) and proteinuria, marked increases in lipid peroxidation, NOX4 and p67phox and decrease in anti-oxidant enzyme. All of these abnormalities were significantly reversed by curcumin. Furthermore, the high-glucose-induced PKC-α and PKC-β1 activities and phosphorylated ERK1/2 was significantly diminished by curcumin. Curcumin also attenuated the expression of TGF-β1, CTGF, osteopontin, p300 and ECM proteins such as fibronectin and type IV collagen. The high-glucose-induced expression of VEGF and its receptor VEGF receptor II (flk-1) was also ameliorated by curcumin. Conclusion: These results prove that curcumin produces dual blockade of both PKC-α and PKC-β1 activities, which suggests that curcumin is a potential adjuvant therapy for the prevention and treatment of diabetic nephropathy.
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- 2011
46. Carvedilol-Afforded Protection against Daunorubicin-Induced Cardiomyopathic Rats In Vivo: Effects on Cardiac Fibrosis and Hypertrophy
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Somasundaram Arumugam, Punniyakoti T. Veeraveedu, Rajarajan Amirthalingam Thandavarayan, Yoshiyasu Kobayashi, Meilei Ma, Kenichi Watanabe, Kenji Suzuki, Vijayakumar Sukumaran, Arun Prasath Lakshmanan, Vivian Soetikno, Sayaka Mito, Wawaimuli Arozal, and Flori R. Sari
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chemistry.chemical_classification ,Cardioprotection ,Reactive oxygen species ,medicine.medical_specialty ,Article Subject ,Cardiac fibrosis ,business.industry ,Daunorubicin ,Pharmacology ,medicine.disease ,medicine.disease_cause ,behavioral disciplines and activities ,Muscle hypertrophy ,Endocrinology ,chemistry ,Internal medicine ,medicine ,Myocardial fibrosis ,business ,Carvedilol ,Oxidative stress ,medicine.drug ,Research Article - Abstract
Anthracyclines, most powerful anticancer agents, suffer from their cardiotoxic effects, which may be due to the induction of oxidative stress. Carvedilol, a third-generation, nonselective β-adrenoreceptor antagonist, possesses both reactive oxygen species (ROS) scavenging and ROS suppressive effects. It showed protective effects against daunorubicin- (DNR-) induced cardiac toxicity by reducing oxidative stress and apoptosis. This study therefore was designed to examine the effects of carvedilol on DNR-induced cardiomyopathic rats, focused on the changes of left ventricular function, cardiac fibrosis, and hypertrophy. Carvedilol increased survival rate, prevented systolic and diastolic dysfunction, and attenuated myocardial fibrosis and hypertrophy. DNR alone treated rats showed upregulated myocardial expression of ANP, PKC-α, OPN, and TGF-β1 and downregulation of GATA-4 in comparison with control, and treatment with carvedilol significantly reversed these changes. The results of the present study add the available evidences on the cardioprotection by carvedilol when associated with anthracyclines and explain the mechanisms underlying the benefits of their coadministration.
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- 2011
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47. Effect of telmisartan in limiting the cardiotoxic effect of daunorubicin in rats
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Wawaimuli Arozal, Yoshifusa Aizawa, Meilei Harima, Punniyakoti T. Veeraveedu, Makoto Kodama, Kenichi Watanabe, Kenji Suzuki, Vijayakumar Sukumaran, and Rajarajan Amirthalingam Thandavarayan
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Cardiac function curve ,Male ,medicine.medical_specialty ,Heart Diseases ,Daunorubicin ,Pharmaceutical Science ,Apoptosis ,Pharmacology ,medicine.disease_cause ,Benzoates ,Ventricular Function, Left ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,Malondialdehyde ,Renin–angiotensin system ,medicine ,Animals ,Telmisartan ,Cardiotoxicity ,Antibiotics, Antineoplastic ,Receptors, Angiotensin ,business.industry ,Myocardium ,Heart ,Angiotensin II ,Rats ,Oxidative Stress ,Endocrinology ,chemistry ,Doxorubicin ,Matrix Metalloproteinase 2 ,Benzimidazoles ,business ,Angiotensin II Type 1 Receptor Blockers ,Oxidative stress ,medicine.drug - Abstract
Objectives Studies have suggested that angiotensin receptor blockers may exert a protective role towards doxorubicin-induced cardiotoxicity, but they have not been extensively investigated in this area. We therefore investigated whether the co-treatment of telmisartan, an angiotensin (Ang II) type-1 receptor blocker, might offer protection against daunorubicin cardiotoxic properties in rats. Methods Daunorubicin was administered at 3 mg/kg/day every other day for 12 days. Telmisartan was administered orally every day for 12 days. Key findings Daunorubicin-treated rats showed cardiac toxicity, evidenced by worsening cardiac function, evaluated by haemodynamic status and echocardiography, elevation of malondialdehyde level and a decreased level of total glutathione peroxidase activity in the heart tissue. These changes were reversed by treatment with telmisartan. Furthermore, telmisartan also downregulated matrix metalloproteinase-2 expression, attenuated the increased protein expression of p22phox, p47phox, p67phox, nuclear factor kappa B and Nox4 in heart tissue, and reduced oxidative-stress-induced DNA damage, which was evaluated by the expression of 8-hydroxydeoxyguanosine. Moreover, telmisartan reduced the myocardial apoptosis induced by daunorubicin. Conclusions The present study indicates that telmisartan may improve cardiac function by inhibiting the action of Ang II via AT-1R, which reverses oxidative stress and myocardial apoptosis. This suggests a beneficial effect of telmisartan treatment in the prevention of daunorubicin-induced cardiotoxicity.
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- 2010
48. Beneficial effects of angiotensin II receptor blocker, olmesartan, in limiting the cardiotoxic effect of daunorubicin in rats
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Yoshifusa Aizawa, Makoto Kodama, Wawaimuli Arozal, Kenichi Watanabe, Kenji Suzuki, Punniyakoti T. Veeraveedu, Rajarajan Amirthalingam Thandavarayan, Hitoshi Tachikawa, Meilei Harima, and Vijayakumar Sukumaran
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Cardiac function curve ,Male ,medicine.medical_specialty ,Angiotensin receptor ,Daunorubicin ,Blotting, Western ,Tetrazoles ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,Medicine ,Animals ,Cardiotoxicity ,Antibiotics, Antineoplastic ,business.industry ,Myocardium ,Imidazoles ,Heart ,General Medicine ,Malondialdehyde ,Angiotensin II ,Immunohistochemistry ,Rats ,Oxidative Stress ,Endocrinology ,chemistry ,business ,Olmesartan ,Angiotensin II Type 1 Receptor Blockers ,Oxidative stress ,medicine.drug - Abstract
The aim was to evaluate the role of the combination of olmesartan, an angiotensin II (Ang II) receptor blocker (ARB), with daunorubicin (DNR) in reducing cardiac toxicity in rats. DNR was administered at a dose of 3 mg/kg/day every other day for 12 days. Olmesartan was administered orally every day for 12 days. Rats treated with DNR alone showed cardiac toxicity as evidenced by worsening cardiac function, elevation of malondialdehyde level in heart tissue and decreased in the level of total glutathione peroxidase activity; treatment with ARB reversed these changes. Furthermore, ARB treatment down-regulated matrix metalloproteinase-2 expression, myocardial expression of Ang II, attenuated the increased protein expressions of p67phox and Nox4 and reduced oxidative stress-induced DNA damage evaluated by expression of 8-hydroxydeoxyguanosine. In conclusion, the result demonstrated that Ang II and oxidative stress play a key role in anthracycline-induced cardiotoxicity and that treatment with ARB will be beneficial against DNR-induced cardiotoxicity.
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- 2010
49. Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions
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Wawaimuli Arozal, Punniyakoti T. Veeraveedu, Rajarajan Amirthalingam Thandavarayan, Meilei Ma, Kenichi Watanabe, Kenji Suzuki, Yoshifusa Aizawa, Makoto Kodama, and Vijayakumar Sukumaran
- Subjects
Male ,medicine.medical_specialty ,Angiotensin receptor ,Receptor expression ,Anti-Inflammatory Agents ,Toxicology ,Kidney ,Kidney Function Tests ,Benzoates ,Antioxidants ,Nephrotoxicity ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Telmisartan ,Creatinine ,Antibiotics, Antineoplastic ,Chemistry ,Angiotensin II ,Daunorubicin ,Receptor, Endothelin A ,Rats ,PPAR gamma ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Benzimidazoles ,Kidney Diseases ,Endothelin receptor ,Angiotensin II Type 1 Receptor Blockers ,medicine.drug - Abstract
Angiotensin II (Ang II) receptor blocker (ARB) suppresses the progression of kidney disease. However, there is limited information regarding the nephroprotective effect of ARB in daunorubicin (DNR)-induced nephrotoxicity in rats. We examined the alteration of the renal Ang II and endothelin-1 (ET-1) receptor expression and the action of telmisartan, an ARB, on DNR-induced nephrotoxicity. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Telmisartan was administered orally every day for 6 weeks. DNR rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdehyde level, and the glutathione peroxidase activity in kidney tissue. These changes were reversed by treatment with telmisartan, which resulted in significant improvement in renal function. Furthermore, telmisartan increased nephrin protein expression, and down-regulated renal expression of Ang II and its receptor Ang II type I. Renal protein expressions of ET-1 and its receptor ET-receptor type A were increased in DNR rats, and treatment with telmisartan attenuated these increased expressions. Telmisartan mediated a further increase in the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). In addition, the expressions of cyclooxygenase-2 and cellular adhesion molecules were increased in DNR rats, which were attenuated by telmisartan. In conclusion, telmisartan has a protective effect on DNR-induced nephrotoxicity through Ang II and ET-1, with the alteration of their receptor expressions, which is associated with its anti-inflammatory and anti-oxidant effects at least in part through PPAR-γ agonistic actions.
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- 2010
50. Arginine vasopressin receptor antagonists (vaptans): pharmacological tools and potential therapeutic agents
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Kenichi Watanabe, Ken'ichi Yamaguchi, Vijayakumar Sukumaran, Suresh S. Palaniyandi, Yutaka Komai, Rajarajan Amirthalingam Thandavarayan, and Punniyakoti T. Veeraveedu
- Subjects
medicine.medical_specialty ,Vasopressin ,Receptors, Vasopressin ,Tolvaptan ,Drug Evaluation, Preclinical ,Pharmacology ,Sodium Potassium Chloride Symporter Inhibitors ,Internal medicine ,Drug Discovery ,medicine ,Humans ,Receptor ,Vasopressin receptor ,Heart Failure ,Clinical Trials as Topic ,business.industry ,Antidiuretic Hormone Receptor Antagonists ,Benzazepines ,medicine.disease ,Arginine Vasopressin ,Endocrinology ,Heart failure ,Conivaptan ,Hyponatremia ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Arginine vasopressin (AVP) attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans because AVP influences renal handling of free water, vasoconstriction and myocyte biology through activation of V 2 and V 1a receptors. Current research is exploring V 2 - and dual V 1a /V 2 receptor antagonism for the treatment of hyponatremia, as well as for the congestion and edema associated with chronic HF, because vasopressin receptor antagonists might offer benefits in comparison with conventional loop diuretics. The purpose of this review is to update the current status of experimental and clinical studies with available vasopressin receptor antagonists (conivaptan and tolvaptan) and their potential role in the treatment of HF and hyponatremia of multiple causes.
- Published
- 2009
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