23 results on '"Nader G."'
Search Results
2. The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure
- Author
-
Zi-jian Xie, Joel Novograd, Yaakov Itzkowitz, Ariel Sher, Yosef D. Buchen, Komal Sodhi, Nader G. Abraham, and Joseph I. Shapiro
- Subjects
Na/K-ATPase ,reactive oxygen species ,coronavirus disease ,heme oxygenase ,obesity ,adipocytes ,Therapeutics. Pharmacology ,RM1-950 - Abstract
This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue—adipocyte specific expression of NaKtide—ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19–porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.
- Published
- 2020
- Full Text
- View/download PDF
3. Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm
- Author
-
Eddie W. Fakhouri, Stephen J. Peterson, Janish Kothari, Ragin Alex, Joseph I. Shapiro, and Nader G. Abraham
- Subjects
SARS-CoV-2 ,COVID-19 ,cytokine storm ,HO-1 ,ACE-2 ,ACE-2R ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are a number of medications that have been tried with some showing early clinical promise. This illness disproportionately affects patients with obesity, a chronic inflammatory disease with a baseline excess of cytokines. The majority of the medications used in the treatment of COVID-19 are metabolized by cytochrome P450 (CYP) enzymes, primarily CYP2D6. This is further complicated by genetic polymorphisms of CYP2D6, HO-1, ACE, and ACE-2. There is a potential role for HO-1 upregulation to treat/prevent cytokine storm. Current therapy must focus on antivirals and heme oxygenase upregulation. Vaccine development will be the only magic bullet.
- Published
- 2020
- Full Text
- View/download PDF
4. Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections
- Author
-
Frank A. D. T. G. Wagener, Peter Pickkers, Stephen J. Peterson, Stephan Immenschuh, and Nader G. Abraham
- Subjects
heme ,heme oxygenase ,SARS-CoV-2 ,inflammation ,COVID-19 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel “proof of concept” studies in the context of COVID-19.
- Published
- 2020
- Full Text
- View/download PDF
5. Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice
- Author
-
Hsin Hsueh Shen, Stephen J. Peterson, Lars Bellner, Abu Choudhary, Lior Levy, Leah Gancz, Ariel Sasson, Joseph Trainer, Rita Rezzani, Abraham Resnick, David E. Stec, and Nader G. Abraham
- Subjects
obesity ,inflammation ,thymoquinone ,omega 3 ,beige adipocyte ,insulin resistance ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5′ adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser307 expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr972), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser307 and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.
- Published
- 2020
- Full Text
- View/download PDF
6. Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model
- Author
-
Shailendra P. Singh, Menachem Greenberg, Yosef Glick, Lars Bellner, Gaia Favero, Rita Rezzani, Luigi Fabrizio Rodella, Kevin Agostinucci, Joseph I. Shapiro, and Nader G. Abraham
- Subjects
antioxidant ,gene-ho-1 ,adiponectin ,adipocytes ,pgc1-α ,hyperglycemia ,hypertension ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.
- Published
- 2020
- Full Text
- View/download PDF
7. Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease
- Author
-
Heather A. Drummond, Zachary L. Mitchell, Nader G. Abraham, and David E. Stec
- Subjects
bilirubin ,carbon monoxide ,hypertension ,kidney injury ,blood pressure ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.
- Published
- 2019
- Full Text
- View/download PDF
8. Pharmacological and Clinical Significance of Heme Oxygenase-1
- Author
-
Stec, David E., primary and Abraham, Nader G., additional
- Published
- 2021
- Full Text
- View/download PDF
9. Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm
- Author
-
Stephen J. Peterson, Eddie W. Fakhouri, Janish Kothari, Ragin Alex, Nader G. Abraham, and Joseph I. Shapiro
- Subjects
0301 basic medicine ,ACE-2R ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,HO-1 ,Cytochrome P450 ,Review ,030204 cardiovascular system & hematology ,Genetic polymorphisms ,Biochemistry ,Virus ,03 medical and health sciences ,0302 clinical medicine ,white adipose tissue ,Downregulation and upregulation ,mitochondrial dysfunction ,medicine ,Molecular Biology ,biology ,CYP2D6 ,business.industry ,SARS-CoV-2 ,lcsh:RM1-950 ,COVID-19 ,RNA virus ,Cell Biology ,medicine.disease ,biology.organism_classification ,Heme oxygenase ,030104 developmental biology ,Cytokine ,lcsh:Therapeutics. Pharmacology ,Immunology ,cytokine storm ,Middle East respiratory syndrome ,business ,Magic bullet ,Cytokine storm ,ACE-2 - Abstract
Coronaviruses are very large RNA viruses that originate in animal reservoirs and include severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS) and other inconsequential coronaviruses from human reservoirs like the common cold. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bat, quickly spread into a global pandemic. This RNA virus has a special affinity for porphyrins. It invades the cell at the angiotensin converting enzyme-2 (ACE-2) receptor and binds to hemoproteins, resulting in a severe systemic inflammatory response, particularly in high ACE-2 organs like the lungs, heart, and kidney, resulting in systemic disease. The inflammatory response manifested by increased cytokine levels and reactive oxygen species results in inhibition of heme oxygenase (HO-1), with a subsequent loss of cytoprotection. This has been seen in other viral illness like human immunodeficiency virus (HIV), Ebola, and SARS/MERS. There are a number of medications that have been tried with some showing early clinical promise. This illness disproportionately affects patients with obesity, a chronic inflammatory disease with a baseline excess of cytokines. The majority of the medications used in the treatment of COVID-19 are metabolized by cytochrome P450 (CYP) enzymes, primarily CYP2D6. This is further complicated by genetic polymorphisms of CYP2D6, HO-1, ACE, and ACE-2. There is a potential role for HO-1 upregulation to treat/prevent cytokine storm. Current therapy must focus on antivirals and heme oxygenase upregulation. Vaccine development will be the only magic bullet.
- Published
- 2020
10. Adipocyte Specific HO-1 Gene Therapy is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model
- Author
-
Luigi Fabrizio Rodella, Lars Bellner, Rita Rezzani, Kevin Agostinucci, Menachem Greenberg, Gaia Favero, Yosef Glick, Shailendra P. Singh, Joseph I. Shapiro, and Nader G. Abraham
- Subjects
0301 basic medicine ,medicine.medical_specialty ,antioxidant ,hypertension ,Physiology ,adipocytes ,Clinical Biochemistry ,Adipokine ,Adipose tissue ,Biochemistry ,Article ,gene-HO-1 ,PGC1-α ,03 medical and health sciences ,Adiposopathy ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Fibrosis ,Adipocyte ,Internal medicine ,medicine ,Molecular Biology ,Adiponectin ,adiponectin ,business.industry ,lcsh:RM1-950 ,Adipocytes ,Antioxidant ,Gene-HO-1 ,Hyperglycemia ,Hypertension ,Cell Biology ,medicine.disease ,3. Good health ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,chemistry ,hyperglycemia ,Adipocyte hypertrophy ,business ,030217 neurology & neurosurgery - Abstract
Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.
- Published
- 2020
- Full Text
- View/download PDF
11. The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure
- Author
-
Xie, Zi-jian, primary, Novograd, Joel, additional, Itzkowitz, Yaakov, additional, Sher, Ariel, additional, Buchen, Yosef D., additional, Sodhi, Komal, additional, Abraham, Nader G., additional, and Shapiro, Joseph I., additional
- Published
- 2020
- Full Text
- View/download PDF
12. Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm
- Author
-
Fakhouri, Eddie W., primary, Peterson, Stephen J., additional, Kothari, Janish, additional, Alex, Ragin, additional, Shapiro, Joseph I., additional, and Abraham, Nader G., additional
- Published
- 2020
- Full Text
- View/download PDF
13. Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections
- Author
-
Wagener, Frank A. D. T. G., primary, Pickkers, Peter, additional, Peterson, Stephen J., additional, Immenschuh, Stephan, additional, and Abraham, Nader G., additional
- Published
- 2020
- Full Text
- View/download PDF
14. Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice
- Author
-
Shen, Hsin Hsueh, primary, Peterson, Stephen J., additional, Bellner, Lars, additional, Choudhary, Abu, additional, Levy, Lior, additional, Gancz, Leah, additional, Sasson, Ariel, additional, Trainer, Joseph, additional, Rezzani, Rita, additional, Resnick, Abraham, additional, Stec, David E., additional, and Abraham, Nader G., additional
- Published
- 2020
- Full Text
- View/download PDF
15. Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model
- Author
-
Singh, Shailendra P., primary, Greenberg, Menachem, additional, Glick, Yosef, additional, Bellner, Lars, additional, Favero, Gaia, additional, Rezzani, Rita, additional, Rodella, Luigi Fabrizio, additional, Agostinucci, Kevin, additional, Shapiro, Joseph I., additional, and Abraham, Nader G., additional
- Published
- 2020
- Full Text
- View/download PDF
16. Pharmacological and Clinical Significance of Heme Oxygenase-1
- Author
-
Nader G. Abraham and David E. Stec
- Subjects
0301 basic medicine ,Physiology ,business.industry ,Clinical Biochemistry ,RM1-950 ,Cell Biology ,030204 cardiovascular system & hematology ,Bioinformatics ,Biochemistry ,Heme oxygenase ,03 medical and health sciences ,Editorial ,n/a ,030104 developmental biology ,0302 clinical medicine ,Medicine ,Clinical significance ,Therapeutics. Pharmacology ,business ,Molecular Biology - Abstract
This Special Issue collates and updates the current knowledge of the pharmacology and clinical applications concerning the enzyme heme oxygenase (HO) [...]
- Published
- 2021
17. The Pivotal Role of Adipocyte-Na K peptide in Reversing Systemic Inflammation in Obesity and COVID-19 in the Development of Heart Failure
- Author
-
Komal Sodhi, Yaakov Itzkowitz, Ariel Sher, Yosef D. Buchen, Nader G. Abraham, Joseph I. Shapiro, Joel Novograd, and Zi Jian Xie
- Subjects
0301 basic medicine ,Na/K-ATPase ,obesity ,medicine.medical_specialty ,Physiology ,adipocytes ,Clinical Biochemistry ,heart failure ,Adipose tissue ,Review ,030204 cardiovascular system & hematology ,Systemic inflammation ,Biochemistry ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Adipocyte ,medicine ,Receptor ,Molecular Biology ,reactive oxygen species ,business.industry ,lcsh:RM1-950 ,Cell Biology ,heme oxygenase ,medicine.disease ,Heme oxygenase ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,coronavirus disease ,chemistry ,Angiotensin-converting enzyme 2 ,medicine.symptom ,business ,Cytokine storm - Abstract
This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue—adipocyte specific expression of NaKtide—ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19–porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.
- Published
- 2020
18. Cold-Pressed Nigella Sativa Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice
- Author
-
Lars Bellner, Ariel Sasson, Lior Levy, Leah Gancz, Stephen J. Peterson, David E. Stec, Abraham Resnick, Rita Rezzani, Joseph Trainer, Abu Choudhary, Nader G. Abraham, and Hsin Hsueh Shen
- Subjects
0301 basic medicine ,obesity ,medicine.medical_specialty ,FGF21 ,Physiology ,Clinical Biochemistry ,thymoquinone ,Adipose tissue ,Beige adipocyte ,Inflammation ,Insulin resistance ,Obesity ,Omega 3 ,Thymoquinone ,White adipose tissue ,030204 cardiovascular system & hematology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,insulin resistance ,Internal medicine ,Adipocyte ,medicine ,Molecular Biology ,Protein kinase B ,PRDM16 ,biology ,Chemistry ,lcsh:RM1-950 ,food and beverages ,Cell Biology ,medicine.disease ,beige adipocyte ,omega 3 ,Insulin receptor ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Endocrinology ,inflammation ,biology.protein ,lipids (amino acids, peptides, and proteins) - Abstract
Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (&omega, 3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and &omega, 3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and &omega, 3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% &omega, 3 in combination for eight weeks. In 3T3-L1 cells, TQ and &omega, 3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and &omega, 3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1&alpha, expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1&alpha, ), Sirt1, and Mfn2. Increased 5&prime, adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and &omega, 3 treatment, which led to increased pAKT and pIRS1 Ser307 expression. In addition to the adipose, TQ and &omega, 3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr972), insulin receptor beta (IR&beta, ), UCP1, and pIRS1 Ser307 and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with &omega, 3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.
- Published
- 2020
19. Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease
- Author
-
Drummond, Heather A., primary, Mitchell, Zachary L., additional, Abraham, Nader G., additional, and Stec, David E., additional
- Published
- 2019
- Full Text
- View/download PDF
20. Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease
- Author
-
David E. Stec, Nader G. Abraham, Heather A. Drummond, and Zachary L. Mitchell
- Subjects
0301 basic medicine ,hypertension ,Physiology ,Bilirubin ,Clinical Biochemistry ,Renal function ,Review ,Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Biochemistry ,carbon monoxide ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Molecular Biology ,business.industry ,lcsh:RM1-950 ,blood pressure ,Cell Biology ,Blood flow ,medicine.disease ,3. Good health ,Heme oxygenase ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Blood pressure ,chemistry ,kidney injury ,bilirubin ,business ,Homeostasis ,Kidney disease - Abstract
Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.
- Published
- 2019
21. Dietary ω-3 Fatty Acid Supplementation Improves Murine Sickle Cell Bone Disease and Reprograms Adipogenesis.
- Author
-
Valenti, Maria Teresa, Mattè, Alessandro, Federti, Enrica, Puder, Mark, Anez-Bustillos, Lorenzo, Deiana, Michela, Cheri, Samuele, Minoia, Arianna, Brugnara, Carlo, Di Paolo, Maria Luisa, Dalle Carbonare, Luca, De Franceschi, Lucia, and Abraham, Nader G.
- Subjects
SICKLE cell anemia ,FATTY acids ,WHITE adipose tissue ,BROWN adipose tissue ,UNCOUPLING proteins ,BONE resorption ,ADIPOSE tissue physiology ,FETAL hemoglobin - Abstract
Sickle cell disease (SCD) is a genetic disorder of hemoglobin, leading to chronic hemolytic anemia and multiple organ damage. Among chronic organ complications, sickle cell bone disease (SBD) has a very high prevalence, resulting in long-term disability, chronic pain and fractures. Here, we evaluated the effects of ω-3 (fish oil-based, FD)-enriched diet vs. ω-6 (soybean oil-based, SD)- supplementation on murine SBD. We exposed SCD mice to recurrent hypoxia/reoxygenation (rec H/R), a consolidated model for SBD. In rec H/R SS mice, FD improves osteoblastogenesis/osteogenic activity by downregulating osteoclast activity via miR205 down-modulation and reduces both systemic and local inflammation. We also evaluated adipogenesis in both AA and SS mice fed with either SD or FD and exposed to rec H/R. FD reduced and reprogramed adipogenesis from white to brown adipocyte tissue (BAT) in bone compartments. This was supported by increased expression of uncoupling protein 1(UCP1), a BAT marker, and up-regulation of miR455, which promotes browning of white adipose tissue. Our findings provide new insights on the mechanism of action of ω-3 fatty acid supplementation on the pathogenesis of SBD and strengthen the rationale for ω-3 fatty acid dietary supplementation in SCD as a complementary therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis.
- Author
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Sanada, Yohei, Tan, Sho Joseph Ozaki, Adachi, Nobuo, Miyaki, Shigeru, Stec, David E., and Abraham, Nader G.
- Subjects
CARTILAGE cells ,CYTOPROTECTION ,HEME ,REACTIVE oxygen species ,OSTEOARTHRITIS ,EXTRACELLULAR matrix ,PROTHROMBIN - Abstract
Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
23. Protective Effects of Kirenol against Lipopolysaccharide-Induced Acute Lung Injury through the Modulation of the Proinflammatory NFκB Pathway and the AMPK2-/Nrf2-Mediated HO-1/AOE Pathway.
- Author
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Lin, Frank Cheau-Feng, Lee, Shiuan-Shinn, Li, Yi-Ching, Ho, Yung-Chuan, Chen, Wen-Ying, Chen, Chun-Jung, Lee, Min-Wei, Yeh, Kun-Lin, Tsai, Stella Chin-Shaw, Kuan, Yu-Hsiang, Stec, David E., and Abraham, Nader G.
- Subjects
LUNG injuries ,SUPEROXIDE dismutase ,LIPOPOLYSACCHARIDES ,PHOSPHORYLATION ,GLUTATHIONE peroxidase ,BRONCHOALVEOLAR lavage - Abstract
Acute lung injury (ALI) is an acute and life-threatening inflammatory disease of the lung parenchyma that is associated with high mortality worldwide. No therapeutic strategies have been developed for the mitigation of the proinflammatory response that characterizes ALI. Kirenol has anti-inflammatory, antiarthritic, and immunoregulatory effects. In the present study, we investigated the protective effects of kirenol against lipopolysaccharides (LPS)-induced ALI in mice. Kirenol reduced the LPS-induced histopathology changes involving edema and thickening of the interstitial or alveolar walls, infiltration of leukocytes, formation of hyaline membrane. Pretreatment with kirenol reduced leukocytes infiltration in bronchoalveolar lavage fluid (BALF), the alveolar-capillary barrier disruption and lipid peroxidation in lung tissues induced by LPS. Kirenol significantly inhibited the secretion of cytokines, IL-1β, IL6, and TNFα, into the BALF of the mice with LPS-induced ALI through NFκB activation. Moreover, kirenol attenuated the downregulation of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and catalase that was induced by LPS. HO-1 expression and the phosphorylation of Nrf2 and AMPK2 were also induced by kirenol. The results indicate that kirenol can be developed as a treatment strategy for ALI, and its effects are induced through the inhibition of the NF-κB proinflammatory pathway and promotion of AMPK2/Nrf2-mediated HO-1 and antioxidant enzymes (AOE) activation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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