scholarly journals CORRECTING GLUTATHIONE DEFICIENCY IN AGING: IMPACT ON MITOCHONDRIA, STRENGTH, INFLAMMATION AND METABOLIC DEFECTS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S415-S416
Author(s):  
Rajagopal Sekhar ◽  
George E Taffet ◽  
Roger Fielding
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Diastolic Heart Failure ◽  
Nutritional Intervention ◽  
Primary Objective ◽  
Double Blind ◽  
Glutathione Deficiency ◽  
The Impact

Abstract Aging is associated with deficiency of Glutathione, the most abundant, intracellular, antioxidant protein, but underlying mechanisms are unknown and interventions limited. This symposium is primarily focused on the results of placebo-controlled, double-blind randomized clinical-trial (RCT) on the impact of correcting Glutathione deficiency in older humans on mitochondrial impairment, oxidative stress, strength, inflammation, and insulin resistance. Dr. Jahoor’s presentation will serve as an introduction by discussing mechanisms underlying Glutathione deficiency and validation of a novel nutritional intervention based on supplementing glycine and N-acetylcysteine (GlyNAC) to correct Glutathione deficiency in older-humans. Dr. Sekhar will present the results of a pilot 16-week pilot randomized, placebo-controlled, double-blind clinical trial in older humans investigating the effect of supplementing GlyNAC (vs. placebo) to improve Glutathione levels and oxidative-stress in 24 older-humans and 12 young-humans on impaired mitochondrial fuel-oxidation (MFO) and other defects. The trial met its primary objective that that GlyNAC supplementation (and not placebo) significantly improved Glutathione deficiency and corrected impaired MFO (and defects in its molecular regulation), and also significantly improved gait-speed (increased 19% increase to match young-humans), muscle-strength, exercise-capacity, and lowered oxidative-stress (80%) inflammation (IL-6 83%, TNF-alpha 58%), and insulin-resistance (68%). Dr. Taffet will discuss age-induced diastolic heart failure, and the effect of supplementing GlyNAC (vs. NAC alone) in aged 24-month old mice with diastolic heart-failure, impaired myocardial MFO and cardiac-inflammation. Collectively this symposium on Glutathione and Aging will highlight the discovery that supplementing GlyNAC to correct Glutathione deficiency in older-humans has significant health benefits, and could be a novel nutritional-intervention in aging.

scholarly journals CORRECTING GLUTATHIONE DEFICIENCY AND MITOCHONDRIAL DYSFUNCTION IN OLDER HUMANS: A RANDOMIZED CLINICAL TRIAL

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S416-S416
Author(s):  
Rajagopal V Sekhar ◽  
Premranjan Kumar ◽  
Jean W Hsu ◽  
James Suliburk ◽  
George E Taffet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Physical Function ◽  
Gait Speed ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Double Blind ◽  
Mitochondrial Fatty Acid ◽  
Glutathione Deficiency

Abstract Aging is associated with impaired mitochondrial fatty-acid oxidation (MFO) due to unknown mechanisms, and interventions are lacking. We hypothesized that impaired MFO in aging occurs due to Glutathione-deficiency and tested this in a randomized, placebo-controlled double-blind clinical-trial in 24 older-humans (71.1y) and 12 young-controls (25.5y) using calorimetry, muscle-biopsy and tracer-protocols. Older-humans received either GlyNAC (Glycine 1.33mmol/kg/d and N-acetylcysteine 0.83mmol/kg/d as Glutathione precursors) or isonitrogenous-placebo for 16-weeks; young-controls received GlyNAC for 2-weeks. Compared to young-controls, older humans had significantly lower Glutathione, impaired MFO, lower gait-speed and physical-function, and higher oxidative-stress, inflammation and insulin-resistance. GlyNAC supplementation in older-humans significantly improved and restored MFO; increased gait-speed (19%,) and physical-function; and decreased oxidative-stress (TBARS 80%), inflammation (IL-6 83%; TNF-alpha 58%), and insulin-resistance (HOMA-IR 68%), but young-controls were unaffected. These data provide proof-of-concept that GlyNAC supplementation could improve the health of older-humans by correcting Glutathione-deficiency and mitochondrial-defects to improve gait-speed, oxidative-stress, inflammation and insulin-resistance.

scholarly journals Nutraceutical Improves Glycemic Control, Insulin Sensitivity, and Oxidative Stress in Hyperglycemic Subjects: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

2020 ◽  
Vol 15 (4) ◽  
pp. 1934578X2091868
Author(s):  
Akkarach Bumrungpert ◽  
Patcharanee Pavadhgul ◽  
Rewadee Chongsuwat ◽  
Surat Komindr
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Glycemic Control ◽  
Lipid Profiles ◽  
Oxidative Stress Markers ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Stress Markers ◽  
And Oxidative Stress

The aim of this research was to investigate the effects of nutraceuticals including bitter melon, fenugreek, cinnamon, alpha-lipoic acid, zinc, biotin, chromium, and cholecalciferol on glycemic control, insulin sensitivity, lipid profiles, oxidative stress, and inflammatory markers in hyperglycemia. The study design was a randomized, double-blind, placebo-controlled trial. Subjects with hyperglycemia were randomly divided into 2 groups. The treatment group ( n = 52) was given a nutraceutical and the control group ( n = 50) was provided with a placebo for 12 weeks. Fasting blood glucose (FBG), hemoglobin A1c (HbA1C), homeostatic model assessment of insulin resistance (HOMA-IR), lipid profiles, biomarkers of oxidative stress, and inflammation were assessed before and after the intervention at 6 weeks and 12 weeks. Nutraceutical supplementation demonstrated a statistically significant decrease in FBG (13.4% and 18.9%), HbA1C (6.5% and 11.3%), and HOMA-IR (28.9% and 35.2%) compared with the placebo. Moreover, low-density lipoprotein-cholesterol (LDL-C) level was significantly reduced in the nutraceutical group (7.1% and 9.3%). Furthermore, the nutraceutical significantly decreased oxidative stress markers, oxidized LDL-C (14.8% and 18.9%) and malondialdehyde (16.6% and 26.2%) compared with the placebo. In conclusion, this nutraceutical can improve glycemic control, insulin resistance, lipid profiles, and oxidative stress markers in hyperglycemic subjects. Therefore, it has the potential to decrease cardiovascular disease risk factors. Clinical trial registration: TCTR20180907001, www.clinicaltrials.in.th.

scholarly journals Randomized double blind clinical trial evaluating the Ellagic acid effects on insulin resistance, oxidative stress and sex hormones levels in women with polycystic ovarian syndrome

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Mahnaz Kazemi ◽  
Fatemeh Lalooha ◽  
Mohammadreza Rashidi Nooshabadi ◽  
Fariba Dashti ◽  
Maria Kavianpour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Sex Hormones ◽  
Polycystic Ovarian Syndrome ◽  
Density Lipoprotein ◽  
Double Blind ◽  
Tnf Α ◽  
The Mean ◽  
Ovarian Syndrome

Abstract Objective The design of this study was due to the report of the antioxidant properties of Ellagic acid (EA) for its evaluation on the Insulin resistance (IR), oxidative stress and sex hormones levels in women with polycystic ovarian syndrome (PCOS). Methods In this randomized, double-blind, placebo-controlled clinical trial, 60 patients were recruited. Patients were randomly allocated consumed a capsule containing 200 mg of EA per day (n = 30) or placebo (n = 30) for 8 weeks. The fasting blood sugar (FBS), insulin, IR, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), total antioxidant capacity (TAC), Malondialdehyde (MDA), C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), sex hormones and anti-mullerian hormone (AMH) were measured at the beginning and end of the study. Result At the end of the study, the mean of FBS, insulin, IR, TC, TG, LDL, MDA, CRP, TNF-α, total testosterone, prolactin and AMH were significantly decreased in the intervention group compared to the placebo group (P < 0.05). Also, there was a significant increase in the mean of TAC after supplementation with EA (P < 0.05). At the end of the study, no significant changes were observed in the mean of anthropometric factors, physical activity and food intake (P > 0.05). Conclusion EA supplementation can be helpful as a diet supplement in women with PCOS through improvement in insulin resistance. This supplement may be used to reduce metabolic disorders in women. Trial registration This study was retrospectively (07–07-2019) registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20141025019669N12).

scholarly journals Reversing Cognitive Decline in Aging: Reversible Mechanistic Defects and a Novel Nutritional Intervention

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 857-857
Author(s):  
Rajagopal Sekhar ◽  
George Taffet
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Older Adults ◽  
Cognitive Decline ◽  
Mitochondrial Dysfunction ◽  
Nutritional Intervention ◽  
Open Label ◽  
Aged Mice ◽  
Naturally Occurring ◽  
Glutathione Deficiency

Abstract Aging is the biggest risk factor for cognitive-decline and Alzheimer’s disease (AD), but underlying mechanisms are not well-understood and interventions are lacking. Cognitive-decline in AD has been associated with deficiency of glutathione, (the most abundant, intracellular, antioxidant protein), elevated oxidative-stress, insulin-resistance and increased inflammation. We identified and reported that glutathione-deficiency and oxidative-stress in older-adults occur due to decreased availability of precursor amino-acids glycine and cysteine, and can be corrected with GlyNAC (a combination of glycine and the cysteine precursor N-acetylcysteine). We hypothesized that cognitive decline in older-adults is linked to glutathione-deficiency, mitochondrial-dysfunction, oxidative-stress, insulin-resistance, and inflammation. The first abstract discusses the rationale and findings of an open-label clinical trial: compared to young-humans, older-adults had cognitive-decline, glutathione-deficiency, mitochondrial-dysfunction, abnormal glucose-metabolism and insulin-resistance, oxidative-stress, endothelial-dysfunction and inflammation. These defects were improved/reversed by supplementing GlyNAC for 24-weeks, but benefits receded on stopping GlyNAC for 12-weeks. The second abstract presents a study in 8 young (20-weeks old) and 16 aged (90-weeks old) wild-type male C57BL/6J mice where we found that aged-mice had naturally-occurring cognitive-impairment, and brain defects in glutathione-deficiency, oxidative-stress, glucose-transport, mitochondrial glucose-oxidation, insulin-resistance, endoplasmic-reticulum stress, autophagy, mitophagy, inflammation, senescence, genomic and telomere damage. Aged-mice received either GlyNAC or isonitrogenous-placebo supplementation for 8-weeks, and only GlyNAC-fed mice improved cognition and brain defects. Collectively these data highlights the discovery of novel and reversible mechanistic defects in older-adults and aged-mice with naturally-occurring cognitive-decline, and identifies that supplementing GlyNAC can improve brain-health and cognition. These findings could have important implications for reversing cognitive-decline in older-adults, and AD.

scholarly journals Obesity and Insulin Resistance Induce Early Development of Diastolic Dysfunction in Young Female Mice Fed a Western Diet

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3632-3642 ◽  
Author(s):  
Camila Manrique ◽  
Vincent G. DeMarco ◽  
Annayya R. Aroor ◽  
Irina Mugerfeld ◽  
Mona Garro ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Diastolic Dysfunction ◽  
Diastolic Heart Failure ◽  
Young Female ◽  
Western Diet ◽  
Insulin Resistant ◽  
And Function ◽  
The Impact

Cardiovascular disease (CVD), including heart failure, constitutes the main source of morbidity and mortality in men and women with diabetes. Although healthy young women are protected against CVD, postmenopausal and diabetic women lose this CVD protection. Obesity, insulin resistance, and diabetes promote heart failure in females, and diastolic dysfunction is the earliest manifestation of this heart failure. To examine the mechanisms promoting diastolic dysfunction in insulin-resistant females, this investigation evaluated the impact of 8 weeks of a high-fructose/high-fat Western diet (WD) on insulin sensitivity and cardiac structure and function in young C57BL6/J female versus male mice. Insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps and two-dimensional echocardiograms were used to evaluate cardiac function. Both males and females developed systemic insulin resistance after 8 weeks of a WD. However, only the females developed diastolic dysfunction. The diastolic dysfunction promoted by the WD was accompanied by increases in collagen 1, a marker of stiffness, increased oxidative stress, reduced insulin metabolic signaling, and increased mitochondria and cardiac microvascular alterations as determined by electron microscopy. Aldosterone (a promoter of cardiac stiffness) levels were higher in females compared with males but were not affected by the WD in either gender. These data suggest a predisposition toward developing early diastolic heart failure in females exposed to a WD. These data are consistent with the notion that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females.

scholarly journals Randomized Double Blind Clinical Trial Evaluating the Ellagic Acid Effects on Insulin Resistance, Oxidative Stress and Sex Hormones Levels in Women With Polycystic Ovarian Syndrome

2021 ◽  
Author(s):  
Mahnaz Kazemi ◽  
Fatemeh Lalooha ◽  
Mohammadreza Rashidi Nooshabadi ◽  
Fariba Dashti ◽  
Maria Kavianpour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Clinical Trial ◽  
Sex Hormones ◽  
Polycystic Ovarian Syndrome ◽  
Density Lipoprotein ◽  
Double Blind ◽  
Tnf Α ◽  
The Mean ◽  
Ovarian Syndrome

Abstract Objective: The design of this study was due to the report of the antioxidant properties of Ellagic acid (EA) for its evaluation on the Insulin resistance (IR), oxidative stress and sex hormones levels in women with polycystic ovarian syndrome (PCOS). Methods: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients were recruited. Patients were randomly allocated consumed a capsule containing 200 mg of EA per day (n = 30) or placebo (n = 30) for 8 weeks. The fasting blood sugar (FBS), insulin, IR, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), total antioxidant capacity (TAC), Malondialdehyde (MDA), C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), sex hormones and anti-mullerian hormone (AMH) were measured at the beginning and end of the study. Result: At the end of the study, the mean of FBS, insulin, IR, TC, TG, LDL, MDA, CRP, TNF-α, total testosterone, prolactin and AMH were significantly decreased in the intervention group compared to the placebo group (P<0.05). Also, there was a significant increase in the mean of TAC after supplementation with EA (P<0.05). At the end of the study, no significant changes were observed in the mean of anthropometric factors, physical activity and food intake (P>0.05). Conclusion: EA supplementation can be helpful as a diet supplement in women with PCOS through improvement in insulin resistance. This supplement may be used to reduce disorders in women, including infertility.Trial Registration: This study was retrospectively (07-07-2019) registered in the Iranian website (www.irct.ir) for registration of clinical trials (IRCT20141025019669N12).

scholarly journals Publisher Correction to: BRAINSTORMING: A study protocol for a randomised double-blind clinical trial to assess the impact of concurrent brain stimulation (tDCS) and working memory training on cognitive performance in Acquired Brain Injury (ABI)

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sara Assecondi ◽  
Rong Hu ◽  
Gail Eskes ◽  
Michelle Read ◽  
Chris Griffiths ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Working Memory ◽  
Brain Injury ◽  
Cognitive Performance ◽  
Acquired Brain Injury ◽  
Working Memory Training ◽  
Memory Training ◽  
Double Blind ◽  
Double Blind Clinical Trial ◽  
The Impact

Following publication of the original article [1], the authors flagged that the article had published with the Acknowledgements erroneously excluded from the declarations at the end of the article.

scholarly journals Rationale and Design of BeatNF2 Trial: A Clinical Trial to Assess the Efficacy and Safety of Bevacizumab in Patients with Neurofibromatosis Type 2 Related Vestibular Schwannoma

2021 ◽  
Vol 28 (1) ◽  
pp. 726-739
Author(s):  
Masazumi Fujii ◽  
Masao Kobayakawa ◽  
Kiyoshi Saito ◽  
Akihiro Inano ◽  
Akio Morita ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Neurofibromatosis Type 2 ◽  
Efficacy And Safety ◽  
Multicenter Clinical Trial ◽  
Double Blind ◽  
Hearing Function ◽  
Initial Intervention

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor’s growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab’s efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.

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