Publications by authors named "Nishant P Visavadiya"

35 Publications

Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia.

Cell Biochem Funct 2021 Jun 15. Epub 2021 Jun 15.

Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida, USA.

Energetically inefficient inter-organ substrate shuttles are proposed contributors to cachexia-related weight loss. Here, we examined glycolytic pathway metabolites, enzyme activity and transport proteins in skeletal muscle, liver and tumours of mice with cachexia-related weight loss induced by colon-26 cancer cells. Skeletal muscle of cachexic mice had increased [L-lactate]/[pyruvate], LDH activity and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle-derived lactate shuttling to liver for use in gluconeogenesis is increased, that is, an increased Cori cycle flux in weight-losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high-affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L-lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L-lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle-derived lactate supply for the tumour (a 'reverse Warburg effect'), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy-regulating tissues may alleviate unintended weight loss in cancer cachexia. SIGNIFICANCE OF THE STUDY: Cachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20-30% of cancer-related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy-regulating tissues may protect against cachexia-related weight loss.
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http://dx.doi.org/10.1002/cbf.3652DOI Listing
June 2021

Resistance Training Diminishes the Expression of Exosome CD63 Protein without Modification of Plasma miR-146a-5p and cfDNA in the Elderly.

Nutrients 2021 Feb 19;13(2). Epub 2021 Feb 19.

Exercise Biochemistry Laboratory, Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, FL 33431, USA.

Aging-associated inflammation is characterized by senescent cell-mediated secretion of high levels of inflammatory mediators, such as microRNA (miR)-146a. Moreover, a rise of circulating cell-free DNA (cfDNA) is also related to systemic inflammation and frailty in the elderly. Exosome-mediated cell-to-cell communication is fundamental in cellular senescence and aging. The plasma changes in exercise-promoted miR-146a-5p, cfDNA, and exosome release could be the key to facilitate intercellular communication and systemic adaptations to exercise in aging. Thirty-eight elderly subjects (28 trained and 10 controls) volunteered in an 8-week resistance training protocol. The levels of plasma miR-146a-5p, cfDNA, and exosome markers (CD9, CD14, CD63, CD81, Flotillin [Flot]-1, and VDAC1) were measured prior to and following training. Results showed no changes in plasma miR-146a-5p and cfDNA levels with training. The levels of exosome markers (Flot-1, CD9, and CD81) as well as exosome-carried proteins (CD14 and VDAC1) remained unchanged, whereas an attenuated CD63 response was found in the trained group compared to the controls. These findings might partially support the anti-inflammatory effect of resistance training in the elderly as evidenced by the diminishment of exosome CD63 protein expression, without modification of plasma miR-146a-5p and cfDNA.
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http://dx.doi.org/10.3390/nu13020665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922765PMC
February 2021

Mitochondrial dynamics and quality control are altered in a hepatic cell culture model of cancer cachexia.

Mol Cell Biochem 2021 Jan 14;476(1):23-34. Epub 2020 Aug 14.

Department of Exercise Science and Health Promotion, Florida Atlantic University, 777 Glades Rd, FH-11A, Rm 128-B, Boca Raton, FL, 33431, USA.

Hepatic mitochondrial function loss is associated with cancer cachexia pathology in vivo. Here, we examined if hepatic mitochondrial defects observed in vivo in the cachexic liver also recapitulate during the in vitro treatment of mouse hepatocytes with tumor conditioned media. In vitro experiments were combined with proteome-wide expression analysis of cachexic liver tissue curated for mitochondrial dynamics and quality control proteins, to determine the fidelity of hepatic mitochondrial maladaptation in cancer cachexia pathology. AML12 hepatocytes were exposed to colon-26 (C26) and Lewis lung carcinoma (LLC) conditioned media for 6-72 h and assayed for cell viability, membrane potential, respiratory function, HO production, total ROS/RNS, and mitochondrial dynamics and quality control proteins by immunoblotting. Liver tissue from cachexic C26 mice was analyzed by TMT-based quantitative proteomics for in vivo comparison. Cell viability, membrane potential, HO production, total ROS/RNS, and respiration were decreased 48-72 h after exposure to C26 and/or LLC. Protein expression of treated hepatocytes and cachexic liver tissue showed altered mitochondrial dynamics and quality control, in a manner that suggests limited fusion and content mixing, but also impaired ability to fragment and clear damaged mitochondria. Two strategies to maintain mitochondrial health, therefore, may not be functioning sufficiently in the cachexic liver. Together these findings imply adverse effects of C26 and LLC exposure on hepatocyte health, due to impaired mitochondrial function and remodeling. Exposure of mouse hepatocytes to tumor conditioned media models aspects of cachexic liver mitochondria dysfunction in vivo and validates the importance of hepatic mitochondrial maladaptation in cancer cachexia pathology.
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http://dx.doi.org/10.1007/s11010-020-03882-9DOI Listing
January 2021

Low-volume acute multi-joint resistance exercise elicits a circulating brain-derived neurotrophic factor response but not a cathepsin B response in well-trained men.

Appl Physiol Nutr Metab 2020 Dec 12;45(12):1332-1338. Epub 2020 Jun 12.

Florida Atlantic University, Department of Exercise Science and Health Promotion, Muscle Physiology Laboratory, Boca Raton, FL 33431, USA.

This study examined if acute multi-joint resistance exercises (RE; back squat, bench press, and deadlift) to volitional failure elicited a postexercise increase in the circulating response of biomarkers associated with neuroprotection. Thirteen males (age: 24.5 ± 3.8 years, body mass: 84.01 ± 15.44 kg, height: 173.43 ± 8.57 cm, training age: 7.1 ± 4.2 years) performed 4 sets to failure at 80% of a 1-repetition maximum on the squat, bench press, and deadlift in successive weeks. The measured biomarkers were brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), cathepsin B (CatB), and interleukin 6 (IL-6). Biomarkers were assessed immediately before and 10-min after exercise. There was a main time effect (pre-exercise: 24.00 ± 0.61 to postexercise: 27.38 ± 0.48 ng/mL; < 0.01) for BDNF with increases in the deadlift ( = 0.01) and bench press ( = 0.01) conditions, but not in the squat condition ( = 0.21). There was a main time effect (pre-exercise: 0.87 ± 0.16 to postexercise: 2.03 ± 0.32 pg/mL; < 0.01) for IL-6 with a significant increase in the squat ( < 0.01), but not the bench press ( = 0.88) and deadlift conditions ( = 0.24). No main time effect was observed for either CatB ( = 0.62) or IGF-1 ( = 0.56). In summary, acute multi-joint RE increases circulating BDNF. Further, this investigation is the first to report the lack of a transient change of CatB to an acute RE protocol. Low-volume RE to failure can increase BDNF. Resistance training does not confer an acute Cat B response.
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http://dx.doi.org/10.1139/apnm-2019-0854DOI Listing
December 2020

Correction to: Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3.

Cell Commun Signal 2020 04 20;18(1):64. Epub 2020 Apr 20.

Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Building 178, Maple Ave, PO Box 70582, Johnson City, TN37614, USA.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12964-020-00577-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168955PMC
April 2020

Hepatic proteome analysis reveals altered mitochondrial metabolism and suppressed acyl-CoA synthetase-1 in colon-26 tumor-induced cachexia.

Physiol Genomics 2020 05 9;52(5):203-216. Epub 2020 Mar 9.

Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida.

Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of nonmuscle organs. The liver exerts major control over systemic metabolism, yet its role in cancer cachexia is not well understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia; ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathway enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient interorgan lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS analysis and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R = 0.73-0.76, < 0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. Findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.
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http://dx.doi.org/10.1152/physiolgenomics.00124.2019DOI Listing
May 2020

Hippocampal Growth Factor and Myokine Cathepsin B Expression following Aerobic and Resistance Training in 3xTg-AD Mice.

Int J Chronic Dis 2020 30;2020:5919501. Epub 2020 Jan 30.

Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida 33431, USA.

Aerobic training (AT) can support brain health in Alzheimer's disease (AD); however, the role of resistance training (RT) in AD is not well established. Aside from direct effects on the brain, exercise may also regulate brain function through secretion of muscle-derived myokines. . This study examined the effects of AT and RT on hippocampal BDNF and IGF-1 signaling, -amyloid expression, and myokine cathepsin B in the triple transgenic (3xTg-AD) model of AD. 3xTg-AD mice were assigned to one of the following groups: sedentary (Tg), aerobic trained (Tg+AT, 9 wks treadmill running), or resistance trained (Tg+RT, 9 wks weighted ladder climbing) ( = 10/group). Rotarod latency and strength were assessed pre- and posttraining. Hippocampus and skeletal muscle were collected after training and analyzed by high-resolution respirometry, ELISA, and immunoblotting. Tg+RT showed greater grip strength than Tg and Tg+AT at posttraining ( < 0.01). Only Tg+AT improved rotarod peak latency ( < 0.01). Hippocampal IGF-1 concentration was ~15% greater in Tg+AT and Tg+RT compared to Tg ( < 0.05); however, downstream signals of p-IGF-1R, p-Akt, p-MAPK, and p-GSK3 were not altered. Cathepsin B, hippocampal p-CREB and BDNF, and hippocampal mitochondrial respiration were not affected by AT or RT. -Amyloid was ~30% lower in Tg+RT compared to Tg ( < 0.05). This data suggests that regular resistance training reduces -amyloid in the hippocampus concurrent with increased concentrations of IGF-1. Both types of training offered distinct benefits, either by improving physical function or by modifying signals in the hippocampus. Therefore, inclusion of both training modalities may address central defects, as well as peripheral comorbidities in AD.
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http://dx.doi.org/10.1155/2020/5919501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011393PMC
January 2020

Aerobic Training Down-Regulates Pentraxin 3 and Pentraxin 3/Toll-Like Receptor 4 Ratio, Irrespective of Oxidative Stress Response, in Elderly Subjects.

Antioxidants (Basel) 2020 Jan 27;9(2). Epub 2020 Jan 27.

Exercise Biochemistry Laboratory, Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, FL 33431, USA.

Reactive oxygen and nitrogen species-mediated cellular aging has been linked to diseases such as atherothrombosis and cancer. Although pentraxin 3 (PTX3) is associated with aging-related diseases via TLR4-dependent anti-inflammatory effects, its relationship with oxidative stress in aging remains to be elucidated. Exercise is proposed as the key intervention for health maintenance in the elderly. This study aimed to examine the association of PTX3 levels with changes in oxidative stress in both plasma and peripheral blood mononuclear cells (PBMCs), following aerobic training in elderly adults. Nine trained and five controls participated in an eight-week aerobic training protocol. Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses were used to determine PTX3, toll-like receptor 4 (TLR4), and levels of oxidative stress biomarkers [3-nitrotyrosine (3NT), 4-hydroxynonenal (4-HNE), reduced glutathione (GSH), protein carbonyl (PC), reactive oxygen/ nitrogen species (ROS/RNS), trolox equivalent antioxidant capacity (TEAC)] in plasma and/or PBMCs. Results showed a down-regulation of PTX3 expression in PBMCs following aerobic training, along with decreased PTX3/TLR4 ratios. Oxidative stress responses in PBMCs remained unchanged with the exercise protocol. Comparable levels of plasma PTX3 and oxidative stress biomarkers were observed in trained vs. control groups. No correlation was found between PTX3 and any oxidative stress biomarkers following training. These findings demonstrated the down-regulation of PTX3 and PTX3/TLR4 ratio, irrespective of oxidative stress response, in elderly adults following eight weeks of aerobic training.
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http://dx.doi.org/10.3390/antiox9020110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070734PMC
January 2020

An exploratory investigation of apoptotic and autophagic responses in peripheral blood mononuclear cells following maximal aerobic exercise in obese individuals.

Arch Physiol Biochem 2019 Sep 28:1-8. Epub 2019 Sep 28.

Exercise Biochemistry Laboratory, Department of Exercise Science and Health Promotion, Florida Atlantic University , Boca Raton , FL , USA.

Autophagy is a critical molecular process in promoting cell survival against apoptosis. This study examined whether maximal aerobic exercise-mediated apoptosis in obesity might be underlying the involvement of autophagy in the peripheral blood mononuclear cells (PBMCs). Twelve healthy male subjects (6 obese and 6 normal-weight) were recruited to participate in a maximal graded exercise test on a treadmill. Obese subjects exhibited a significantly lower Bax, but a higher Bcl-2 protein level in conjunction with a reduced Bax/Bcl-2 AUCi compared to normal-weight subjects following exercise. Furthermore, a greater LC3-II/LC3-I ratio and LC3-II/LC3-I AUCi was observed in obese subjects compared to normal-weight subjects. LC3-II/LC3-I AUCi was also positively associated with obesity-associated parameters (BMI, waist/hip circumference, and fasting insulin level), but was negatively correlated with Bax/Bcl-2 AUCi. These findings demonstrate that maximal aerobic exercise differentially mediates the intrinsic apoptotic pathway and autophagic activity in human PBMCs isolated from obese compared to normal-weight individuals.
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http://dx.doi.org/10.1080/13813455.2019.1671875DOI Listing
September 2019

Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia.

Am J Physiol Regul Integr Comp Physiol 2019 07 24;317(1):R68-R82. Epub 2019 Apr 24.

Department of Exercise Science and Health Promotion, Florida Atlantic University , Boca Raton, Florida.

In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of nonmuscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple chronic diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 weight-stable mice and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). The respiratory control ratio [(RCR) an index of oxidative phosphorylation (OXPHOS) coupling efficiency] was low in WAT during the induction of cachexia because of high nonphosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice because of reduced OXPHOS. Liver RCR was further reduced with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 was inversely correlated with RCR in the liver ( = -0.547, < 0.01). Liver cardiolipin increased in moderate and severe cachexia, suggesting this early event may also contribute to mitochondrial uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia, at complex I. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and may contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an under-recognized role of liver and WAT mitochondrial function in cancer cachexia and suggest mitochondrial function of multiple tissues to be therapeutic targets.
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http://dx.doi.org/10.1152/ajpregu.00028.2019DOI Listing
July 2019

Time course of recovery is similar for the back squat, bench press, and deadlift in well-trained males.

Appl Physiol Nutr Metab 2019 Oct 19;44(10):1033-1042. Epub 2019 Feb 19.

Florida Atlantic University, Department of Exercise Science and Health Promotion, Muscle Physiology Laboratory, Boca Raton, FL 33431, USA.

This study examined the time course of recovery following resistance exercise sessions in the back squat, bench press, and deadlift. Twelve well-trained males (age: 24.5 ± 3.8 years, body mass: 84.01 ± 15.44 kg, training age: 7.1 ± 4.2 years) performed 4 sets to failure at 80% of a 1-repetition maximum (1RM) on the squat, bench press, and deadlift in successive weeks. The bench press was always performed in week 2 with the squat and deadlift order counterbalanced between weeks 1 and 3. Indirect muscle damage and performance fatigue was assessed immediately before and after exercise and at 24 h, 48 h, 72 h, and 96 h postexercise. Outcome measures included limb swelling, joint range of motion, delayed onset muscle soreness, average concentric velocity (ACV) at 70% of 1RM, creatine kinase, lactate dehydrogenase, and cell-free DNA (cfDNA). Most measures demonstrated a main time effect ( < 0.05) within conditions; however, no between condition ( > 0.05) differences existed. ACV decreased in the squat condition for up to 72 h ( = 0.02, -8.61%) and in the bench press ( < 0.01, -26.69%) immediately postexercise but did not decline during the deadlift condition ( > 0.05). There was a main time effect for increased cfDNA in the squat ( < 0.01) and bench press ( < 0.05), but not the deadlift ( = 0.153). Further, immediately postexercise increases in cfDNA were directly related ( < 0.05) to changes in ACV in all 3 conditions. These results suggest that the deadlift does not result in greater muscle damage and recovery time than the squat and bench press following volume-type training in well-trained men. Further, acute changes in cfDNA may predict performance during the recovery period.
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http://dx.doi.org/10.1139/apnm-2019-0004DOI Listing
October 2019

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells.

Medchemcomm 2018 Sep 26;9(9):1491-1501. Epub 2018 Jul 26.

Biodesign Center for BioEnergetics , Arizona State University , Tempe , AZ 85287 , USA . Email:

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously ( and ) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, and , exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.
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http://dx.doi.org/10.1039/c8md00274fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148561PMC
September 2018

Chemical synthesis of lipophilic methylene blue analogues which increase mitochondrial biogenesis and frataxin levels.

Data Brief 2018 Oct 31;20:1105-1114. Epub 2018 Aug 31.

Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.

As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), we have prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich's ataxia cells [1]. This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.
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http://dx.doi.org/10.1016/j.dib.2018.08.156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139889PMC
October 2018

Lipophilic methylene blue analogues enhance mitochondrial function and increase frataxin levels in a cellular model of Friedreich's ataxia.

Bioorg Med Chem 2018 07 4;26(12):3359-3369. Epub 2018 May 4.

Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Presently, a series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich's ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production. Our results suggest that analogue 5, emerging from the initial structure of the parent compound methylene blue (MB), represents a promising lead structure and lacks the cytotoxicity associated with the parent compound MB.
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http://dx.doi.org/10.1016/j.bmc.2018.05.005DOI Listing
July 2018

Post-Injury Treatment with NIM811 Promotes Recovery of Function in Adult Female Rats after Spinal Cord Contusion: A Dose-Response Study.

J Neurotrauma 2018 02 6;35(3):492-499. Epub 2017 Nov 6.

Department of Neuroscience, Spinal Cord and Brain Injury Research Center, University of Kentucky Medical Center , Lexington, Kentucky.

Mitochondrial homeostasis is essential for maintaining cellular function and survival in the central nervous system (CNS). Mitochondrial function is significantly compromised after spinal cord injury (SCI) and is associated with accumulation of high levels of calcium, increased production of free radicals, oxidative damage, and eventually mitochondrial permeability transition (mPT). The formation of the mPT pore (mPTP) and subsequent mPT state are considered to be end stage events in the decline of mitochondrial integrity, and strategies that inhibit mPT can limit mitochondrial demise. Cyclosporine A (CsA) is thought to inhibit mPT by binding to cyclophilin D and has been shown to be effective in models of CNS injury. CsA, however, also inhibits calcineurin, which is responsible for its immunosuppressive properties. In the present study, we conducted a dose-response examination of NIM811, a nonimmunosuppressive CsA analog, on recovery of function and tissue sparing in a rat model of moderate to severe SCI. The results of our experiments revealed that NIM811 (10 mg/kg) significantly improved open field locomotor performance, while the two higher doses tested (20 and 40 mg/kg) significantly improved return of reflexive bladder control and significantly decreased the rostral-caudal extent of the lesion. Taken together, these results demonstrate the ability of NIM811 to improve recovery of function in SCI and support the role of protecting mitochondrial function as a potential therapeutic target.
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http://dx.doi.org/10.1089/neu.2017.5167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793953PMC
February 2018

Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells.

Cell Signal 2017 08 8;36:154-162. Epub 2017 May 8.

Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, PO Box 70582, Johnson City, TN 37614, USA. Electronic address:

Excessive endoplasmic reticulum (ER) stress leads to cell loss in many diseases, e.g., contributing to endothelial cell loss after spinal cord injury. Here, we determined whether ER stress-induced mitochondrial dysfunction could be explained by interruption of the focal adhesion kinase (FAK)-mitochondrial STAT3 pathway we recently discovered. ER stress was induced in brain-derived mouse bEnd5 endothelial cells by thapsigargin or tunicamycin and caused apoptotic cell death over a 72h period. In concert, ER stress caused mitochondrial dysfunction as shown by reduced bioenergetic function, loss of mitochondrial membrane potential and increased mitophagy. ER stress caused a reduction in mitochondrial phosphorylated S727-STAT3, known to be important for maintaining mitochondrial function. Normal activation or phosphorylation of the upstream cytoplasmic FAK was also reduced, through mechanisms that involve tyrosine phosphatases and calcium signaling, as shown by pharmacological inhibitors, bisperoxovanadium (bpV) and 2-aminoethoxydiphenylborane (APB), respectively. APB mitigated the reduction in FAK and STAT3 phosphorylation, and improved endothelial cell survival caused by ER stress. Transfection of cells rendered null for STAT3 using CRISPR technology with STAT3 mutants confirmed the specific involvement of S727-STAT3 inhibition in ER stress-mediated cell loss. These data suggest that loss of FAK signaling during ER stress causes mitochondrial dysfunction by reducing the protective effects of mitochondrial STAT3, leading to endothelial cell death. We propose that stimulation of the FAK-STAT3 pathway is a novel therapeutic approach against pathological ER stress.
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http://dx.doi.org/10.1016/j.cellsig.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589129PMC
August 2017

Erratum to: Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3.

Cell Commun Signal 2017 03 27;15(1):11. Epub 2017 Mar 27.

Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Building 178, Maple Ave, PO Box 70582, Johnson City, TN37614, USA.

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http://dx.doi.org/10.1186/s12964-017-0167-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369200PMC
March 2017

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3.

Cell Commun Signal 2016 12 15;14(1):32. Epub 2016 Dec 15.

Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Building 178, Maple Ave, PO Box 70582, Johnson City, TN37614, USA.

Background: STAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof.

Methods: Cultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts.

Results: Vitronectin-dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and αvβ3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period.

Conclusion: These data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators.
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http://dx.doi.org/10.1186/s12964-016-0157-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159999PMC
December 2016

Altered Cerebellar Circuitry following Thoracic Spinal Cord Injury in Adult Rats.

Neural Plast 2016 18;2016:8181393. Epub 2016 Jul 18.

Department of Physical Medicine and Rehabilitation, Spinal Cord and Brain Injury Research Center, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA.

Cerebellar function is critical for coordinating movement and motor learning. However, events occurring in the cerebellum following spinal cord injury (SCI) have not been investigated in detail. We provide evidence of SCI-induced cerebellar synaptic changes involving a loss of granule cell parallel fiber input to distal regions of the Purkinje cell dendritic tree. This is accompanied by an apparent increase in synaptic contacts to Purkinje cell proximal dendrites, presumably from climbing fibers originating in the inferior olive. We also observed an early stage injury-induced decrease in the levels of cerebellin-1, a synaptic organizing molecule that is critical for establishing and maintaining parallel fiber-Purkinje cell synaptic integrity. Interestingly, this transsynaptic reorganizational pattern is consistent with that reported during development and in certain transgenic mouse models. To our knowledge, such a reorganizational event has not been described in response to SCI in adult rats. Regardless, the novel results of this study are important for understanding SCI-induced synaptic changes in the cerebellum, which may prove critical for strategies focusing on promoting functional recovery.
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http://dx.doi.org/10.1155/2016/8181393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967704PMC
September 2017

Cellular and subcellular oxidative stress parameters following severe spinal cord injury.

Redox Biol 2016 08 30;8:59-67. Epub 2015 Dec 30.

Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA.

The present study undertook a comprehensive assessment of the acute biochemical oxidative stress parameters in both cellular and, notably, mitochondrial isolates following severe upper lumbar contusion spinal cord injury (SCI) in adult female Sprague Dawley rats. At 24h post-injury, spinal cord tissue homogenate and mitochondrial fractions were isolated concurrently and assessed for glutathione (GSH) content and production of nitric oxide (NO(•)), in addition to the presence of oxidative stress markers 3-nitrotyrosine (3-NT), protein carbonyl (PC), 4-hydroxynonenal (4-HNE) and lipid peroxidation (LPO). Moreover, we assessed production of superoxide (O2(•-)) and hydrogen peroxide (H2O2) in mitochondrial fractions. Quantitative biochemical analyses showed that compared to sham, SCI significantly lowered GSH content accompanied by increased NO(•) production in both cellular and mitochondrial fractions. SCI also resulted in increased O2(•-) and H2O2 levels in mitochondrial fractions. Western blot analysis further showed that reactive oxygen/nitrogen species (ROS/RNS) mediated PC and 3-NT production were significantly higher in both fractions after SCI. Conversely, neither 4-HNE levels nor LPO formation were increased at 24h after injury in either tissue homogenate or mitochondrial fractions. These results indicate that by 24h post-injury ROS-induced protein oxidation is more prominent compared to lipid oxidation, indicating a critical temporal distinction in secondary pathophysiology that is critical in designing therapeutic approaches to mitigate consequences of oxidative stress.
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http://dx.doi.org/10.1016/j.redox.2015.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712315PMC
August 2016

Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury.

Exp Neurol 2015 Mar 3;265:84-93. Epub 2015 Jan 3.

Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY 40536, USA; Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA; Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA. Electronic address:

Traumatic brain injury (TBI) is a major cause of death and disability. However, the molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI; however, the underlying mechanisms and consequences are not clear. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally, and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs show altered expression following TBI; however, the relevance of mitochondria in these pathways is unknown. Here, we present evidence supporting the association of miRNA with hippocampal mitochondria, as well as changes in mitochondria-associated miRNA expression following a controlled cortical impact (CCI) injury in rats. Specifically, we found that the miRNA processing proteins Argonaute (AGO) and Dicer are present in mitochondria fractions from uninjured rat hippocampus, and immunoprecipitation of AGO associated miRNA from mitochondria suggests the presence of functional RNA-induced silencing complexes. Interestingly, RT-qPCR miRNA array studies revealed that a subset of miRNA is enriched in mitochondria relative to cytoplasm. At 12h following CCI, several miRNAs are significantly altered in hippocampal mitochondria and cytoplasm. In addition, levels of miR-155 and miR-223, both of which play a role in inflammatory processes, are significantly elevated in both cytoplasm and mitochondria. We propose that mitochondria-associated miRNAs may play an important role in regulating the response to TBI.
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http://dx.doi.org/10.1016/j.expneurol.2014.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346439PMC
March 2015

Differential proteomic analysis of acute contusive spinal cord injury in rats using iTRAQ reagent labeling and LC-MS/MS.

Neurochem Res 2013 Nov 21;38(11):2247-55. Epub 2013 Aug 21.

Departments of Physical Medicine and Rehabilitation, Anatomy and Neurobiology, and the Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA.

In this experimental study, differential labeling with isobaric tags for relative and absolute quantitation (iTRAQ) reagents followed by liquid chromatography (LC) and tandem mass spectrometry (MS/MS) proteomic approach was used to investigate differences in the proteome of rat spinal cord at 24 h following a moderate contusion injury. Spinal cord protein samples from the injury epicenter (or from sham controls) were trypsinized and differentially labeled with iTRAQ isotopic reagents. The differentially labeled samples were then combined into one sample mixture, separated by LC, and analyzed using MS/MS. Proteins were quantified by comparing the peak areas of iTRAQ reporter fragment ions in MS/MS spectra. The outcome of this analysis revealed that proteins involved in ubiquitination, endocytosis and exocytosis, energy metabolism, inflammatory response, oxidative stress, cytoskeletal disruption, and vascular damage were significantly altered at 24 h following spinal cord injury (SCI). This study demonstrates the utility of the iTRAQ method in proteomic studies and provides further insights into secondary events that occur during acute times following SCI.
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http://dx.doi.org/10.1007/s11064-013-1132-yDOI Listing
November 2013

Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage.

Toxicol In Vitro 2013 Mar 23;27(2):788-97. Epub 2012 Dec 23.

Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY 40536-0509, United States.

Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group.
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http://dx.doi.org/10.1016/j.tiv.2012.12.011DOI Listing
March 2013

Ameliorative effects of herbal combinations in hyperlipidemia.

Oxid Med Cell Longev 2011 15;2011:160408. Epub 2011 Sep 15.

BRD School of Biosciences, Sardar Patel University, Vallabh Vidyanagar, India.

The roots of Glycyrrhiza glabra, Withania somnifera, Asparagus racemosus, and Chlorophytum borivilianum and seeds of Sesamum indicum are ayurvedic medicinal plants used in India to treat several ailments. Our previous studies indicated that these plants possess hypolipidemic and antioxidant potential. The present study was aimed at investigating the composite effects of these plants on hypercholesterolemic rats. Three different combinations (5 gm%, given for four weeks) used in this study effectively reduced plasma and hepatic lipid profiles and increased fecal excretion of cholesterol, neutral sterol, and bile acid along with increasing the hepatic HMG-CoA reductase activity and bile acid content in hypercholesterolemic rats. Further, all three combinations also improved the hepatic antioxidant status (catalase, SOD, and ascorbic acid levels) and plasma total antioxidant capacity with reduced hepatic lipid peroxidation. Overall, combination I had the maximum effect on hypercholesterolemic rats followed by combinations II and III due to varying concentrations of the different classes of phytocomponents.
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http://dx.doi.org/10.1155/2011/160408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173889PMC
January 2012

High glucose upregulates upstream stimulatory factor 2 in human renal proximal tubular cells through angiotensin II-dependent activation of CREB.

Nephron Exp Nephrol 2011 1;117(3):e62-70. Epub 2010 Sep 1.

Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536-0200, USA.

Background/aims: We have previously demonstrated that a transcription factor, upstream stimulatory factor 2 (USF2), regulates glucose-induced thrombospondin 1 expression and transforming growth factor-β activity in mesangial cells, and plays an important role in diabetic glomerulopathy. In this study, we determined whether USF2 expression in renal proximal tubular cells is regulated by glucose and contributes to diabetic tubulointerstitial fibrosis.

Methods: Human renal proximal tubular cells (HK-2 cells) were treated with normal- or high-glucose medium for 24 h. After treatment, real-time PCR or immunoblotting was used to determine the expression of USF2 and other components of the renin-angiotensin system in HK-2 cells.

Results: High glucose upregulated USF2 expression and increased extracellular matrix accumulation in HK-2 cells; both were inhibited by siRNA-mediated USF2 knockdown. In addition, high glucose stimulated angiotensinogen and renin expression, increased renin activity, and resulted in increased angiotensin II formation. Treatment of HK-2 cells with an angiotensin II receptor 1 (AT1) blocker--losartan--prevented high-glucose-induced USF2 expression and high-glucose-enhanced phosphorylation of CREB (cAMP response element-binding protein).

Conclusion: Our data established that high glucose stimulated USF2 expression in HK-2 cells, at least in part, through angiotensin II-AT1-dependent activation of CREB, which can contribute to diabetic tubulointerstitial fibrosis.
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http://dx.doi.org/10.1159/000320593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948662PMC
June 2011

Purified c-phycoerythrin: safety studies in rats and protective role against permanganate-mediated fibroblast-DNA damage.

J Appl Toxicol 2010 Aug;30(6):542-50

Laboratoire de Biologie Intégrative, CEA Saclay, 91191 Gif Sur Yvette, France.

We have evaluated in vitro cytotoxicity of cyanobacterial phycoerythrin (C-PE) on three human cell lines by cell proliferation and neutral red uptake assays. No toxic effects of C-PE were observed to any of the cell lines tested. The protective role of purified C-PE to potassium permanganate-mediated human fibroblast-DNA damage was assessed by comet assay at 0 (control), 10 and 20 microg C-PE ml(-1) doses in pre-, simultaneous and post-mutagen exposure conditions. Significant DNA damage was detected only in post-mutagen exposure conditions. Our findings confirmed that the C-PE is non-toxic and provides protection against permanganate-mediated DNA damage. The preliminary acute (2000 mg C-PE kg(-1) body weight, b.w.) and 90 day sub-chronic (0, 5, 15 and 25 mg C-PE kg(-1) b.w./day) oral toxicity studies of purified C-PE in male albino rats showed no mortality or treatment-related major clinical signs, and all the doses of C-PE were well tolerated. The no observed adverse effect level and no observed effect level were found to be 15 and 5 mg C-PE kg(-1) b.w./day respectively.
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http://dx.doi.org/10.1002/jat.1524DOI Listing
August 2010

Chlorophytum borivilianum as potential terminator of free radicals in various in vitro oxidation systems.

Drug Chem Toxicol 2010 Apr;33(2):173-82

BRD School of Biosciences, Sardar Patel Maidan, Vadtal Road, Satellite Campus, Postbox 39, Sardar Patel University, Vallabh Vidyanagar 388 120, Gujarat, India.

Chlorophytum borivilianum is a very popular herb in traditional Indian medicine and used as a potent "Rasayana" drug in "Ayurveda" as a rejuvenator. Currently, a large body of evidence supports the key role of free radicals in diverse pathological conditions such as aging and atherosclerosis. The present investigation essentially focuses on the comprehensive account of in vitro antioxidant activity exerted by C.borivilianum root extracts (i.e., aqueous and ethanolic), to clarify the pharmacological antagonism of chemicals/metals-mediated oxidation. Graded-dose (25 to 1000 microg/ml) of aqueous extract exhibited higher antioxidant potency as evidenced by powerful nitric oxide, superoxide, hydroxyl, DPPH and ABTS(*+) radicals scavenging activity along with reducing capacity (Fe(3+)/ferricyanide complex and FRAP assays), metal chelating ability, as well as markedly suppressed the lipid peroxidation in mitochondrial fractions as compared to ethanolic extract. Further, aqueous extract significantly decreased (P < 0.05) copper-mediated human serum and kinetics of LDL oxidation, as demonstrated by prolongation of lag phase time with decline of oxidation rate, conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances. In addition, the total polyphenol and flavonoid contents of aqueous extract were higher than that of ethanolic extract, which indicated a positive correlation between antioxidant activity and contents of total phenols. The IC(50) values of both extracts were also compared with appropriate antioxidant standards. Overall, aqueous extract of C.borivilianum root has significant powerful antioxidant activity and may favorably affect atherosclerosis risk status by reducing LDL oxidation susceptibility.
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http://dx.doi.org/10.3109/01480540903311068DOI Listing
April 2010

Free radical scavenging and antiatherogenic activities of Sesamum indicum seed extracts in chemical and biological model systems.

Food Chem Toxicol 2009 Oct 14;47(10):2507-15. Epub 2009 Jul 14.

BRD School of Biosciences, Sardar Patel Maidan, Sardar Patel University, Vallabh Vidyanagar 388 120, Gujarat, India.

An emerging consensus underscores the importance of oxidative events in vascular disease including excess production of reactive oxygen/nitrogen species (ROS/RNS), in addition to lipoprotein oxidation. Sesamum indicum has long been used extensively as a traditional food. The aim of present study was to evaluate antioxidant action of aqueous and ethanolic seed extracts from S. indicum using various in vitro ROS/RNS generated chemical and biological models. Results demonstrated that the graded-dose (25-1000 microg/ml) of aqueous and ethanolic extracts markedly scavenged the nitric oxide, superoxide, hydroxyl, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals and, showed metal chelating ability as well as reducing capacity in Fe(3+)/ferricyanide complex and ferric reducing antioxidant power assays. In biological models, both extracts were found to inhibit metal-induced lipid peroxidation in mitochondrial fractions, human serum and LDL oxidation models. In lipoprotein kinetics study, both extracts significantly (P<0.05) increased lag phase time along with reduced oxidation rate and conjugated dienes production. Ethanolic extract of S. indicum showed higher amounts of total polyphenol and flavonoid content as compared to their counterpart. The IC(50) values of both extracts were compared with respective antioxidant standards. Overall, ethanolic extract of S. indicum possess strong antioxidant capacity and offering effective protection against LDL oxidation susceptibility.
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http://dx.doi.org/10.1016/j.fct.2009.07.009DOI Listing
October 2009

Evaluation of antioxidant and anti-atherogenic properties of Glycyrrhiza glabra root using in vitro models.

Int J Food Sci Nutr 2009 22;60 Suppl 2:135-49. Epub 2009 Apr 22.

BRD School of Biosciences, Sardar Patel Maidan, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India.

The aim of present study was to evaluate antioxidant property of Glycyrrhiza glabra root extracts using in vitro models. The dose-dependent aqueous and ethanolic extracts demonstrated the scavenging activity against nitric oxide (concentration that caused 50% inhibition of nitric oxide radicals [IC(50)]=72 and 62.1 microg/ml, respectively), superoxide (IC(50)=64.2 and 38.4 microg/ml, respectively), hydroxyl (IC(50)=81.9 and 63 microg/ml, respectively), DPPH (IC(50)=43.6 and 28.3 microg/ml, respectively) and ABTS(*+) (IC(50)=77.3 and 57.2 microg/ml, respectively) radicals. Further, both extracts showed strong reducing power and iron-chelating capacities. In the Fe(2+)/ascorbate system, both extracts were found to inhibit mitochondrial fraction lipid peroxidation. In copper-catalyzed human serum and low-density lipoprotein oxidation models, both extracts significantly (P<0.05) lengthened the lag phase along with a decline in the oxidation rate, conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substance formation. In conclusion, ethanolic extract of G. glabra possess considerable antioxidant activity and protective effect against the human lipoprotein oxidative system.
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http://dx.doi.org/10.1080/09637480902877998DOI Listing
March 2012

Attenuation of diabetic complications by C-phycoerythrin in rats: antioxidant activity of C-phycoerythrin including copper-induced lipoprotein and serum oxidation.

Br J Nutr 2009 Jul 5;102(1):102-9. Epub 2009 Jan 5.

BRD School of Biosciences, Sardar Patel Maidan, Vadtal Road, Satellite Campus, Post Box 39, Sardar Patel University, Vallabh Vidyanagar 388 120, Gujarat, India.

In the present study, the protective role of purified C-phycoerythrin (C-PE) against diabetic complications and Cu-mediated lipoprotein oxidation was evaluated. C-PE (25 and 50 mg/kg body weight per d) was administered to experimental streptozotocin-nicotinamide-induced type 2 diabetic male rats for 28 d. C-PE treatment successfully ameliorated diabetic complications by decreasing food intake, organ weights, serum concentrations of glucose, cholesterol, TAG, VLDL-cholesterol, creatinine, uric acid and thiobarbituric acid-reactive substances (TBARS), with increases in body weight, Hb, total protein, bilirubin and ferric-reducing ability of plasma values. Hepatic and renal tissues demonstrated significant decreases in TBARS, lipid hydroperoxide and conjugated diene contents, with increases in superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin E and vitamin C levels. Furthermore, the 4-week ex vivo and in vitro administration of C-PE (0.5 and 1.0 mg/ml) indicated a decrease in Cu-mediated serum oxidation. The kinetics of the LDL oxidation profile showed significant prolongation of the lag phase with declines in oxidation rate, conjugated dienes, lipid hydroperoxide and TBARS. Results indicated the involvement of C-PE in the amelioration of diabetic complications by significant reductions in oxidative stress and oxidised LDL-triggered atherogenesis.
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http://dx.doi.org/10.1017/S0007114508162973DOI Listing
July 2009
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