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author:("Ravi, baranya")
1.  The Bioenergetic Health Index: a new concept in mitochondrial translational research 
Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the ‘canary in the coal mine’ by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value–the Bioenergetic Health Index (BHI)–can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.
doi:10.1042/CS20140101
PMCID: PMC4202728  PMID: 24895057
aging; cardiovascular disease; haplotype; hepatotoxicity; neurodegenerative disease; oxidative stress; reserve capacity; BHI, Bioenergetic Health Index; ETC, electron transport chain; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HNE, hydroxynonenal; LDA, linear discriminant analysis; mtDNA, mitochondrial DNA; OCR, oxygen consumption rate; RNS, reactive nitrogen species; ROS, reactive oxygen species
2.  A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers☆ 
Redox Biology  2014;2:206-210.
The assessment of metabolic function in cells isolated from human blood for treatment and diagnosis of disease is a new and important area of translational research. It is now becoming clear that a broad range of pathologies which present clinically with symptoms predominantly in one organ, such as the brain or kidney, also modulate mitochondrial energetics in platelets and leukocytes allowing these cells to serve as “the canary in the coal mine” for bioenergetic dysfunction. This opens up the possibility that circulating platelets and leukocytes can sense metabolic stress in patients and serve as biomarkers of mitochondrial dysfunction in human pathologies such as diabetes, neurodegeneration and cardiovascular disease. In this overview we will describe how the utilization of glycolysis and oxidative phosphorylation differs in platelets and leukocytes and discuss how they can be used in patient populations. Since it is clear that the metabolic programs between leukocytes and platelets are fundamentally distinct the measurement of mitochondrial function in distinct cell populations is necessary for translational research.
Graphical abstract
Highlights
•Monocytes, lymphocytes, neutrophils and platelets have distinct bioenergetic programs that regulate energy production.•Platelets and monocytes exhibit a high level of aerobic glycolysis and mitochondrial respiration.•Lymphocytes have a low glycolytic capacity while neutrophils have little or no detectable oxidative phosphorylation.•The levels of mitochondrial complex IV and III subunits differ substantially between lymphocytes, monocytes and platelets.
doi:10.1016/j.redox.2013.12.026
PMCID: PMC3909784  PMID: 24494194
ROS/RNS, reactive oxygen species/reactive nitrogen species; OCR, oxygen consumption rate; ECAR, extracellular acidification rate; XF, extracellular flux analyzer; Reserve capacity; Oxidative stress; Metabolic shift; Biomarker; Leukocytes; Platelets
3.  Antiangiogenic Activity of rPAI-123 Promotes Vasa Vasorum Regression in Hypercholesterolemic Mice Through a Plasmin-Dependent Mechanism 
Circulation Research  2011;108(12):1419-1428.
Rationale
The antiangiogenic activity of rPAI-123, a truncated plasminogen activator inhibitor-1 (PAI-1) protein, induces vasa vasorum collapse and significantly reduces plaque area and plaque cholesterol in hypercholesterolemic low-density lipoprotein receptor–deficient/apolipoprotein B48–deficient mice.
Objective
The objective of this study was to examine rPAI-123–stimulated mechanisms that cause vasa vasorum collapse.
Methods and Results
The rPAI-123 protein opposed PAI-1 antiproteolytic function by stimulating a 1.6-fold increase in plasmin activity compared with the saline-treated counterpart. The increased proteolytic activity corresponded to increased activity of matrix metalloproteinase-3 and degradation of fibrin(ogen), nidogen, and perlecan in the adventitia of descending aortas. PAI-1 activity was reduced by 48% in response to rPAI-123; however, PAI-1 protein expression levels were similar in the rPAI-123– and saline-treated hypercholesterolemic mice. Coimmunoprecipitation assays demonstrated a novel PAI-1–plasminogen complex in protein from the descending aorta of rPAI-123– and saline-treated mice, but complexed PAI-1 was 1.6-fold greater in rPAI-123–treated mice. Biochemical analyses demonstrated that rPAI-123 and PAI-1 binding interactions with plasminogen increased plasmin activity and reduced PAI-1 antiproteolytic activity.
Conclusions
We conclude that rPAI-123 causes regression or collapse of adventitial vasa vasorum in hypercholesterolemic mice by stimulating an increase in plasmin activity. The rPAI-123–enhanced plasmin activity was achieved through a novel mechanism by which rPAI-123 and PAI-1 bound plasminogen in a cooperative manner to increase plasmin activity and reduce PAI-1 activity.
doi:10.1161/CIRCRESAHA.111.246249
PMCID: PMC3370683  PMID: 21546607
angiogenesis; atherosclerosis; vasa vasorum; plasminogen activator inhibitor-1; proteolysis
4.  Long-Term Cultured Human Term Placenta-Derived Mesenchymal Stem Cells of Maternal Origin Displays Plasticity 
Stem Cells International  2012;2012:174328.
Mesenchymal stem cells (MSCs) are an alluring therapeutic resource because of their plasticity, immunoregulatory capacity and ease of availability. Human BM-derived MSCs have limited proliferative capability, consequently, it is challenging to use in tissue engineering and regenerative medicine applications. Hence, placental MSCs of maternal origin, which is one of richest sources of MSCs were chosen to establish long-term culture from the cotyledons of full-term human placenta. Flow analysis established bonafied MSCs phenotypic characteristics, staining positively for CD29, CD73, CD90, CD105 and negatively for CD14, CD34, CD45 markers. Pluripotency of the cultured MSCs was assessed by in vitro differentiation towards not only intralineage cells like adipocytes, osteocytes, chondrocytes, and myotubules cells but also translineage differentiated towards pancreatic progenitor cells, neural cells, and retinal cells displaying plasticity. These cells did not significantly alter cell cycle or apoptosis pattern while maintaining the normal karyotype; they also have limited expression of MHC-II antigens and are Naive for stimulatory factors CD80 and CD 86. Further soft agar assays revealed that placental MSCs do not have the ability to form invasive colonies. Taking together all these characteristics into consideration, it indicates that placental MSCs could serve as good candidates for development and progress of stem-cell based therapeutics.
doi:10.1155/2012/174328
PMCID: PMC3329664  PMID: 22550499
5.  Anaphase Catastrophe is a Target for Cancer Therapy 
Neoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can be exploited to disrupt tumor cell growth potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically kills tumor cells with more than two centrosomes. This death program can occur after genetic or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologically induced for apoptotic death of cancer cells. This is an appealing mechanism to engage for cancer therapy and prevention.
doi:10.1158/1078-0432.CCR-10-1178
PMCID: PMC3061280  PMID: 21288923
anaphase catastrophe; cyclin E-Cdk2; multipolar anaphase; anti-neoplastic target
6.  Expression of human amyloid precursor protein in the skeletal muscles of Drosophila results in age- and activity-dependent muscle weakness 
BMC Physiology  2011;11:7.
Background
One of the hallmarks of Alzheimer's disease, and several other degenerative disorders such as Inclusion Body Myositis, is the abnormal accumulation of amyloid precursor protein (APP) and its proteolytic amyloid peptides. To better understand the pathological consequences of inappropriate APP expression on developing tissues, we generated transgenic flies that express wild-type human APP in the skeletal muscles, and then performed anatomical, electrophysiological, and behavioral analysis of the adults.
Results
We observed that neither muscle development nor animal longevity was compromised in these transgenic animals. However, human APP expressing adults developed age-dependent defects in both climbing and flying. We could advance or retard the onset of symptoms by rearing animals in vials with different surface properties, suggesting that human APP expression-mediated behavioral defects are influenced by muscle activity. Muscles from transgenic animals did not display protein aggregates or structural abnormalities at the light or transmission electron microscopic levels. In agreement with genetic studies performed with developing mammalian myoblasts, we observed that co-expression of the ubiquitin E3 ligase Parkin could ameliorate human APP-induced defects.
Conclusions
These data suggest that: 1) ectopic expression of human APP in fruit flies leads to age- and activity-dependent behavioral defects without overt changes to muscle development or structure; 2) environmental influences can greatly alter the phenotypic consequences of human APP toxicity; and 3) genetic modifiers of APP-induced pathology can be identified and analyzed in this model.
doi:10.1186/1472-6793-11-7
PMCID: PMC3112101  PMID: 21518451
amyloid precursor protein (APP); Drosophila; muscle; mitochondria; electron microscopy; apoptosis; Parkin
7.  Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors 
Cancer research  2010;70(1):319-328.
Aromatase (CYP19) is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors (AIs) are established endocrine therapy for post-menopausal women with breast cancer. DNA samples were obtained from 52 women pre- and post-AI treatment in the neoadjuvant setting. 82 breast cancer and 19 normal breast samples were resequenced to test the hypothesis that single nucleotide polymorphisms (SNPs) in the CYP19 gene might contribute to response to neoadjuvant AI therapy. There were no differences in CYP19 sequence between tumor and germline DNA in the same patient. Forty-eight CYP19 SNPs were identified, with four being novel when compared with previous resequencing data. Genotype-phenotype association studies performed with levels of aromatase activity, estrone, estradiol and tumor size pre- and post-AI treatment indicated that two tightly linked SNPs, rs6493497 and rs7176005 in the 5’-flanking region of CYP19 exon 1.1, were significantly associated with a greater change in aromatase activity after AI treatment. A follow-up study in 200 women with early breast cancer treated with adjuvant anastrozole showed that these same two SNPs were also associated with higher plasma estradiol levels pre- and post-AI treatment. Electrophoretic mobility shift and reporter gene assays confirmed the potential functional effects of these two SNPs on transcription regulation. These studies provide insight into the role of common genetic polymorphisms in CYP19 in variation in response to AIs by breast cancer patients.
doi:10.1158/0008-5472.CAN-09-3224
PMCID: PMC2804935  PMID: 20048079
Aromatase; aromatase inhibitors; CYP19; gene resequencing; SNP; functional genomics; genotype-phenotype association
8.  Methods for defining distinct bioenergetic profiles in platelets, lymphocytes, monocytes, and neutrophils, and the oxidative burst from human blood 
Peripheral blood mononuclear cells and platelets have long been recognized as having the potential to act as sensitive markers for mitochondrial dysfunction in a broad range of pathological conditions. However, the bioenergetic function of these cells has not been examined from the same donors, yet this is important for the selection of cell types for translational studies. Here, we demonstrate the measurement of cellular bioenergetics in isolated human monocytes, lymphocytes, and platelets, including the oxidative burst from neutrophils and monocytes from individual donors. With the exception of neutrophils, all cell types tested exhibited oxygen consumption that could be ascribed to oxidative phosphorylation with each having a distinct bioenergetic profile and distribution of respiratory chain proteins. In marked contrast, neutrophils were essentially unresponsive to mitochondrial respiratory inhibitors indicating that they have a minimal requirement for oxidative phosphorylation. In monocytes and neutrophils, we demonstrate the stimulation of the oxidative burst using phorbol 12-myristate 13-acetate and its validation in normal human subjects. Taken together, these data suggest that selection of cell type from blood cells is critical for assessing bioenergetic dysfunction and redox biology in translational research.
doi:10.1038/labinvest.2013.53
PMCID: PMC3674307  PMID: 23528848
mitochondria; neutrophils; peripheral blood mononuclear cells; respiratory burst

Results 1-8 (8)