scholarly journals Melatonin combination with perindopril alleviated doxorubicin cardiac toxicity in L-NAME hypertensive rats: comparative study with perindopril

2019 ◽  
Author(s):  
Takwa Mohammed Abdul Salam ◽  
Amany Helmy Hasanin ◽  
Wesam El-Bakly ◽  
Mona Hussein Raafat ◽  
Nesreen Omar ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cardiac Toxicity ◽  
Diastolic Pressure ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Protective Effects ◽  
Hypertensive Rats ◽  
Tnf Α ◽  
Doxorubicin Cardiotoxicity ◽  
Percentage Area

Introduction: Doxorubicin is a highly effective anticancer agent with serious cardiotoxic effects. Hypertension is considered as a major risk factor for doxorubicin cardiotoxicity. It should be noted that about one-third of cancer patients have hypertension, and melatonin can have cardio-protective effects. The present study aimed to further investigate the possible beneficial effects of melatonin co-administration to perindopril against doxorubicin cardiotoxicity in hypertensive rats. Method: Rats were randomly assigned to naïve group and L-NAME group, which was further subdivided into untreated, doxorubicin, doxorubicin/perindopril, doxorubicin/melatonin and doxorubicin/perindopril/melatonin subgroups. Cardiac functions, CK-MB, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and cardiac percentage area of collagen fibers were evaluated. Results: Combining melatonin with perindopril to doxorubicin produced significant decreases in left ventricular end diastolic pressure, malondialdehyde, TNF-α, and TGF-β. It resulted in significant increases in left ventricular dP/dtmax and SOD, in addition to apparent improvement in cardiac histopathology with a significant decrease in percentage area of collagen deposition compared to perindopril alone. Conclusion: Co-administration of melatonin to perindopril in hypertensive rats who received doxorubicin alleviated doxorubicin cardiac toxicity more than using perindopril alone. These effects could be explained by the reported antihypertensive, anti-inflammatory, anti-oxidant, and anti-fibrotic effects of melatonin.

scholarly journals Melatonin combination with perindopril alleviated doxorubicin cardiac toxicity in L-NAME hypertensive rats: comparative study with perindopril

2019 ◽  
Author(s):  
Takwa Mohammed Abdul Salam ◽  
Amany Helmy Hasanin ◽  
Wesam El-Bakly ◽  
Mona Hussein Raafat ◽  
Nesreen Omar ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Cardiac Toxicity ◽  
Diastolic Pressure ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Protective Effects ◽  
Hypertensive Rats ◽  
Tnf Α ◽  
Doxorubicin Cardiotoxicity ◽  
Percentage Area

Introduction: Doxorubicin is a highly effective anticancer agent with serious cardiotoxic effects. Hypertension is considered as a major risk factor for doxorubicin cardiotoxicity. It should be noted that about one-third of cancer patients have hypertension, and melatonin can have cardio-protective effects. The present study aimed to further investigate the possible beneficial effects of melatonin co-administration to perindopril against doxorubicin cardiotoxicity in hypertensive rats. Method: Rats were randomly assigned to naïve group and L-NAME group, which was further subdivided into untreated, doxorubicin, doxorubicin/perindopril, doxorubicin/melatonin and doxorubicin/perindopril/melatonin subgroups. Cardiac functions, CK-MB, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and cardiac percentage area of collagen fibers were evaluated. Results: Combining melatonin with perindopril to doxorubicin produced significant decreases in left ventricular end diastolic pressure, malondialdehyde, TNF-α, and TGF-β. It resulted in significant increases in left ventricular dP/dtmax and SOD, in addition to apparent improvement in cardiac histopathology with a significant decrease in percentage area of collagen deposition compared to perindopril alone. Conclusion: Co-administration of melatonin to perindopril in hypertensive rats who received doxorubicin alleviated doxorubicin cardiac toxicity more than using perindopril alone. These effects could be explained by the reported antihypertensive, anti-inflammatory, anti-oxidant, and anti-fibrotic effects of melatonin.

Abstract 146: Disruption of Nox2 and TNFRp55/p75 Eliminates Anisomycin-Induced Preconditioning Effect in the Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ting C Zhao ◽  
Ling Zhang ◽  
Tai-Liang Guo
Keyword(s):  
Infarct Size ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Kinase Assay ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride ◽  
Transient Activation ◽  
Novel Approach ◽  
Tnf Α ◽  
A Subunit

Background: Transient activation of p38 through anisomycin is demonstrated to precondition the heart against myocardial injury. However, it remains unknown whether specific TNF-α receptor (TNFR) p55/p75 and Nox2, a subunit of NADPH-oxidase are involved in this event. Objective: We sought to investigate whether the genetic disruption of TNFRp55/p75 and Nox2 eliminates cardioprotection elicited by anisomycin and whether p38-dependent activation of Nox2 stimulates TNFR to ultimately achieve protective effects. Methods: Adult wild type and p55/p75 -/- and Nox2 -/- mice received intraperitoneal injections of anisomycin (0.1mg/kg), a potent activator of p38. The hearts were subjected to 30 min myocardial ischemia /30 min reperfusion in the Langendorff perused heart after twenty four hours. Left ventricular function was measured and infarct size was determined by triphenyltetrazolium chloride. Myocardial TNF-α protein, Nox2 and superoxides releases were detected. Gel kinase assay was employed to detect the effect of p38 on Nox2 phosphorylation. Results: Activation of p38 through anisomycin produces marked improvements in the recovery of left ventricular end diastolic pressure, rate pressure products, and the reduction of myocardial infarction, which were completely abrogated by disruption of Nox2 and TNFR p55/p75. Genetic disruption of Nox2 and TNFR p55/p75 abolished the effect of anisomycin-induced reduction of infarct size. Ansiomycin induced the production of TNFα, which was abrogated in Nox2 -/- mice. Notably, activation of p38 resulted in the phosphorylation of Nox2. Conclusion: Taken together, these results indicate that stimulation of the Nox2 and TNFR p55/p75 pathway is a novel approach to anisomycin-induced cardioprotection.

Ganoderic Acid A Inhibits Bleomycin-Induced Lung Fibrosis in Mice

Pharmacology ◽  
2020 ◽  
Vol 105 (9-10) ◽  
pp. 568-575
Author(s):  
Gaoyan Wen ◽  
Tian Li ◽  
Hua He ◽  
Xianmei Zhou ◽  
Jia Zhu
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Protective Effect ◽  
Transforming Growth Factor ◽  
Dry Weight ◽  
Transforming Growth Factor Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Ganoderic Acid ◽  
Tnf Α

<b><i>Background:</i></b> To study the protective effects of ganoderic acid A (GAA) on bleomycin (BLM)-induced pulmonary fibrosis. <b><i>Methods:</i></b> ICR mice were intratracheally instilled with BLM to induce pulmonary fibrosis on day 0. Then the mice were orally given GAA (25, 50 mg/kg) or dexamethasone (2 mg/kg). After treatment for 21 days, the mice were sacrificed. Wet dry weight (W/D) ratio of lung was used to detect pulmonary edema. Myeloperoxidase (MPO), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining was used to evaluate the pathological changes. The levels of transforming growth factor β (TGF-β), phosphorylated-smad3 (p-smad3), p-IκB, and p-nuclear factor-kappa B (NF-κB) in lung tissue were detected by western blot. <b><i>Results:</i></b> GAA treatment significantly improved MPO activity, W/D ratio, and lung histopathology. The protective effect of GAA may be related to downregulation of TNF-α, IL-1β, IL-6, MDA and upregulation of SOD. In addition, GAA significantly decreased the levels of TGF-β, p-smad3, p-IκB, and p-NF-κB, compared with those in BLM group. <b><i>Conclusion:</i></b> GAA has protective effect on BLM-induced lung injury, and TGF-β/Smad-3/NF-κB signaling pathway may play an important role in the pathogenesis of BLM-induced lung injury.

scholarly journals The Effects of Rice Husk Liquid Smoke in Porphyromonas gingivalis-Induced Periodontitis

2021 ◽  
Author(s):  
Theresia Indah Budhy ◽  
Ira Arundina ◽  
Meircurius Dwi Condro Surboyo ◽  
Anisa Nur Halimah
Keyword(s):  
Growth Factor ◽  
Porphyromonas Gingivalis ◽  
Rice Husk ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Control Group ◽  
Proliferation Markers ◽  
Liquid Smoke ◽  
Tnf Α ◽  
Factor Α

Abstract Objectives The purpose of this study is to analyze the effects of rice husk liquid smoke in Porphyromonas gingivalis-induced periodontitis in the inflammatory and proliferation marker such as nuclear factor kappa β (NF-kB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β), fibroblast growth factor 2 (FGF2), collagen type 1 (COL-1) expression, and the number of macrophages, lymphocytes, and fibroblasts. Materials and Methods Rice husk liquid smoke is obtained by the pyrolysis process. Porphyromonas gingivalis-induced periodontitis in 20 μL phosphate-buffered saline containing 1 × 109 CFU was injected into the lower anterior gingival sulcus of Wistar rats. The periodontitis was then treated with 20 μL/20 g body weight of rice husk liquid smoke once a day for 2 and 7 days, respectively. After treatment, the bone and lower anterior gingival sulcus were analyzed with immunohistochemistry and hematoxylin–eosin staining. Results The treatment of periodontitis with rice husk liquid smoke showed a lower NF-kB, TNF-α, and IL-6 expression and a higher TGF-β, FGF2, and COL-1 expression than the control after treatment for 2 and 7 days (p < 0.05), respectively. The number of macrophages and fibroblasts was also higher when compared with the control group (p < 0.05), but the number of lymphocytes was lower than the control (p < 0.05). Conclusion Rice husk liquid smoke showed its effects on Porphyromonas gingivalis-induced periodontitis with a decrease in inflammatory markers and an increase in proliferation markers. The development of a rice husk liquid smoke periodontitis treatment is promising.

Differential Mechanisms of Plasminogen Activator Inhibitor-1 Gene Activation by Transforming Growth Factor-β and Tumor Necrosis Factor-α in Endothelial Cells

2001 ◽  
Vol 86 (12) ◽  
pp. 1563-1572 ◽  
Author(s):  
Yan Chen ◽  
Joanne Sloan-Lancaster ◽  
David Berg ◽  
Mark Richardson ◽  
Brian Grinnell ◽  
...  
Keyword(s):  
Map Kinases ◽  
Transforming Growth Factor ◽  
Gene Activation ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β ◽  
Promoter Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (SERPIN) specific for tissue-type and urokinase-like plasminogen activators. High plasma PAI-1 activity is a risk factor for thrombotic diseases. Due to the short half-life of PAI-1, regulation of PAI-1 gene expression and secretion of active PAI-1 into the blood stream is important for hemostatic balance. We have investigated transcriptional control of PAI-1 gene expression in bovine aortic endothelial cells (BAECs) and human cell lines using PAI-1 5’ promoter-luciferase reporter assays. Contrary to the cytokine-induced up-regulation of PAI-1 mRNA and protein levels, we found that only transforming growth factor-β (TGF-β) was efficient in inducing PAI-1 promoter activation. Tissue necrosis factor-α (TNF-α) induced a small luciferase activity with the 2.5 kb PAI-1 promoter, but not with the PAI-800/4G/5G and p3TP-lux promoters. Next we investigated whether a lack of response to TNF-α was due to deficient signaling pathways. BAECs responded to TNF-α with robust NFκB promoter activation. TGF-β activated the p38 MAP kinase, while TNF-α activated both the SAPK/JNK and p38 MAP kinases. The ERK1/2 MAP kinases were constitutively activated in BAECs. BAEC therefore responded to TNF-α stimulation with activation of the MAP kinases and the NFκB transcriptional factors. We further measured the messenger RNA stability under the influence by TGF-β and TNF-α and found no difference. PAI-1 gene activation by TNF-α apparently is yet to be defined for the location of the response element and/or the signaling pathway, while TGF-β is the most important cytokine for PAI-1 transcriptional activation through its 5’ proximal promoter.

DNA enzyme targeting TNF-α mRNA improves hemodynamic performance in rats with postinfarction heart failure

2001 ◽  
Vol 281 (5) ◽  
pp. H2211-H2217 ◽  
Author(s):  
Per Ole Iversen ◽  
Gunnar Nicolaysen ◽  
Mouldy Sioud
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Diastolic Pressure ◽  
Substantial Reduction ◽  
Left Ventricular ◽  
Lung Weight ◽  
Cleavage Activity ◽  
Arterial Blood ◽  
Modified Dna ◽  
Tnf Α

Tumor necrosis factor-α (TNF-α) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-α mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-α in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-α in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-α mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.

Exposure to febrile temperature modifies endothelial cell response to tumor necrosis factor-α

2001 ◽  
Vol 90 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Jeffrey D. Hasday ◽  
Douglas Bannerman ◽  
Sirhan Sakarya ◽  
Alan S. Cross ◽  
Ishwar S. Singh ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Gm Csf ◽  
Tnf Α ◽  
Neutrophil Adherence ◽  
Endothelial Cell Response ◽  
Factor Α ◽  
Necrosis Factor

Fever is an important regulator of inflammation that modifies expression and bioactivity of cytokines, including tumor necrosis factor (TNF)-α. Pulmonary vascular endothelium is an important target of TNF-α during the systemic inflammatory response. In this study, we analyzed the effect of a febrile range temperature (39.5°C) on TNF-α-stimulated changes in endothelial barrier function, capacity for neutrophil binding and transendothelial migration (TEM), and cytokine secretion in human pulmonary artery endothelial cells (EC). Permeability for [14C]BSA tracer was increased by treatment with TNF-α, and this effect was augmented by incubating EC at 39.5°C. Treating EC with 2.5 U/ml TNF-α stimulated an increase in subsequent neutrophil adherence and TEM. Incubating EC at 39.5°C caused a 30% increase in TEM but did not modify the enhancement of neutrophil adherence or TEM by TNF-α treatment. Analysis of cytokine expression in EC cultures exposed to TNF-α at either 37° or 39.5°C revealed three patterns of temperature and TNF-α responsiveness. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-8 were not detectable in untreated EC but were increased after TNF-α exposure, and this increase was enhanced at 39.5°C. IL-6 expression was also increased with TNF-α exposure, but IL-6 expression was lower in 39.5°C EC cultures. Transforming growth factor-β1was constitutively expressed, and its expression was not influenced either by TNF-α or exposure to 39.5°C. These data demonstrate that clinically relevant shifts in body temperature might cause important changes in the effects of proinflammatory cytokines on the endothelium.

scholarly journals Possible mechanism of the cardio-renal protective effects of AVE-0991, a non-peptide Mas-receptor agonist, in diabetic rats

2012 ◽  
Vol 13 (3) ◽  
pp. 334-340 ◽  
Author(s):  
Kulwinder Singh ◽  
Kuldeepak Sharma ◽  
Manjeet Singh ◽  
PL Sharma
Keyword(s):  
Blood Pressure ◽  
Receptor Agonist ◽  
Diastolic Pressure ◽  
Left Ventricular Pressure ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Protective Effects ◽  
Mas Receptor ◽  
Arterial Blood

Hypothesis: This study was designed to investigate the cardio-renal protective effect of AVE-0991, a non-peptide Mas-receptor agonist, and A-779, a Mas-receptor antagonist, in diabetic rats. Materials and methods: Wistar rats treated with streptozotocin (50 mg/kg, i.p., once), developed diabetes mellitus after 1 week. After 8 weeks, myocardial functions were assessed by measuring left ventricular developed pressure (LVDP), rate of left ventricular pressure development (d p/d tmax), rate of left ventricular pressure decay (d p/d tmin) and left ventricular end diastolic pressure (LVEDP) on an isolated Langendorff’s heart preparation. Further, mean arterial blood pressure (MABP) was measured by using the tail-cuff method. Assessment of renal functions and lipid profile was carried out using a spectrophotometer. Results: The administration of streptozotocin to rats produced persistent hyperglycaemia, dyslipidaemia and hypertension which consequently produced cardiac and renal dysfunction in 8 weeks. AVE0991 treatment produced cardio-renal protective effects, as evidenced by a significant increase in LVDP, d p/d tmax, d p/d tmin and a significant decrease in LVEDP, BUN, and protein urea. Further, AVE-0991 treatment for the first time has been shown to reduce dyslipidaemia and produced antihyperglycaemic activity in streptozotocin-treated rats. However, MABP and creatinine clearance remained unaffected with AVE-0991 treatment. Conclusions: AVE-0991 produced cardio-renal protection possibly by improving glucose and lipid metabolism in diabetic rats, independent of its blood pressure lowering action.

Abstract 297: Cardiac Transforming-growth-factor β-stimulated Clone 22 Gene Expression By Hypertrophic Stimuli

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Annina Kelloniemi ◽  
Jani Aro ◽  
Elina Koivisto ◽  
Heikki Ruskoaho ◽  
Jaana Rysä
Keyword(s):  
Growth Factor ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Pressure Overload ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Ang Ii ◽  
Sd Rats

Objectives: Transforming-growth-factor β-stimulated clone 22 (TSC-22) is a leucine zipper protein expressed in many tissues and possessing various transcription-modulating activities. However, its function in the heart remains largely unknown. The aim of the present study was to characterize the cardiac TSC-22 expression. Methods: Acute pressure overload was accomplished in conscious Sprague-Dawley (SD) rats by intravenous infusion of arginine 8 -vasopressin (AVP, 0.05 μg/kg/min) for 4 hours and subcutaneous infusion of angiotensin II (Ang II, 33 μg/kg/h) with and without Ang II receptor type 1 blocker losartan (400 μg/kg/h) by using osmotic minipumps for 2 weeks. Adenovirus-mediated intramyocardial gene transfer of TSC-22 was performed into left ventricle (LV) of SD rats. Experimental myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Cultured neonatal rat ventricular myocytes (NRVM) were treated with endothelin-1 (ET-1, 100 nM). Results: A significant 1.6-fold increase ( P <0.05) in LV TSC-22 mRNA levels was noted already after 1 hour AVP infusion. Moreover, Ang II infusion markedly upregulated TSC-22 expression, LV mRNA levels being highest at 6 hours (11-fold, P <0.001). Simultaneous infusion of losartan completely abolished Ang II-induced increase in TSC-22 mRNA levels. Adenovirus-mediated gene transfer of TSC-22 into LV resulted a 1.9-fold ( P <0.001) increase in TSC-22 mRNA levels, accompanied by upregulated BNP mRNA levels (1.4-fold, P <0.01). In response to experimental MI, TSC-22 mRNA levels were elevated 4.1-fold ( P <0.001) at 1 day and 1.9-fold ( P <0.05) at 4 weeks. In cultured NRVM, ET-1 treatment increased TSC-22 mRNA levels from 1 h to 24 h, the greatest increase being observed at 12 h (2.7-fold, P <0.001). TSC-22 protein levels were upregulated from 4 h to 24 h with the highest increase at 24 h (4.7-fold, P <0.01). Conclusion: These results indicate that TSC-22 expression is rapidly activated in response to pressure overload, MI and in ET-1 treated cultured NRVM. Moreover, adenovirus-mediated overexpression of TSC-22 mRNA was associated with elevated left ventricular BNP mRNA levels.

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