Honors & Awards

  • DAAD Travel fellowship, Cyceron, University of Caen, Caen, France (2013)
  • Travel Award - ISTH 2013, University of Giessen (2013)
  • DAAD Travel fellowship, Theodor Kocher Institute, Bern, Switzerland (2013)
  • DAAD STIBET teaching assistantship, Courses in Bioinformatics - University of Giessen (2010-2013)

Professional Education

  • Doctor of Philosophy, Justus-Liebig-Universität Gießen, Biochemistry, Neuroscience (2014)
  • Master of Science, University of Abertay Dundee, Biotechnology (2006)
  • Bachelor of Science, University of Pune, Microbiology, Chemistry, Zoology (2005)

Stanford Advisors

All Publications

  • Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Haileselassie, B., Mukherjee, R., Joshi, A. U., Napier, B. A., Massis, L. M., Ostberg, N., Queliconi, B. B., Monack, D., Bernstein, D., Mochly-Rosen, D. 2019; 130: 160–69
  • Proteasome-Dependent Regulation of Distinct Metabolic States During Long-Term Culture of Human iPSC-Derived Cardiomyocytes. Circulation research Ebert, A., Joshi, A. U., Andorf, S., Dai, Y., Sampathkumar, S., Chen, H., Li, Y., Garg, P., Toischer, K., Hasenfuβ, G., Mochly Rosen, D., Wu, J. C. 2019


    The immature presentation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is currently a challenge for their application in disease modeling, drug screening, and regenerative medicine. Long-term culture is known to achieve partial maturation of iPSC-CMs. However, little is known about the molecular signaling circuitries that govern functional changes, metabolic output, and cellular homeostasis during long-term culture of iPSC-CMs.We aimed to identify and characterize critical signaling events that control functional and metabolic transitions of cardiac cells during developmental progression, as recapitulated by long-term culture of iPSC-CMs.We combined transcriptomic sequencing with pathway network mapping in iPSC-CMs that were cultured until a late time point, day 200 (D200), in comparison to a medium time point, day 90 (D90), and an early time point, day 30 (D30). Transcriptomic landscapes of long-term cultured iPSC-CMs allowed mapping of distinct metabolic stages during development of maturing iPSC-CMs. Temporally divergent control of mitochondrial metabolism was found to be regulated by cAMP/protein kinase A (PKA)- and proteasome-dependent signaling events. The PKA/proteasome-dependent signaling cascade was mediated downstream by heat shock protein 90 (Hsp90), which in turn modulated mitochondrial respiratory chain proteins and their metabolic output. During long-term culture, this circuitry was found to initiate upregulation of iPSC-CM metabolism, resulting in increased cell contractility that reached a maximum at the D200 time point.Our results reveal a PKA/proteasome- and Hsp90-dependent signaling pathway that regulates mitochondrial respiratory chain proteins and determines cardiomyocyte energy production and functional output. These findings provide deeper insight into signaling circuitries governing metabolic homeostasis in iPSC-CMs during developmental progression.

    View details for DOI 10.1161/CIRCRESAHA.118.313973

    View details for PubMedID 31104567

  • Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nature neuroscience Joshi, A. U., Minhas, P. S., Liddelow, S. A., Haileselassie, B., Andreasson, K. I., Dorn, G. W., Mochly-Rosen, D. 2019; 22 (10): 1635–48


    In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

    View details for DOI 10.1038/s41593-019-0486-0

    View details for PubMedID 31551592

  • Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. Journal of molecular and cellular cardiology Haileselassie, B., Mukherjee, R., Joshi, A. U., Napier, B. A., Massis, L. M., Ostberg, N. P., Queliconi, B. B., Monack, D., Bernstein, D., Mochly-Rosen, D. 2019


    Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. Although recent literature implicates dynamin related protein 1 (Drp1) and its mitochondrial adaptor fission 1 (Fis1) in the development of pathologic fission and mitochondrial failure in neurodegenerative disease, little is known about the role of Drp1/Fis1 interaction in the context of sepsis-induced cardiomyopathy. Our study tests the hypothesis that Drp1/Fis1 interaction is a major driver of sepsis-mediated pathologic fission, leading to mitochondrial dysfunction in the heart.H9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to evaluate changes in mitochondrial membrane potential, oxidative stress, cellular respiration, and mitochondrial morphology. Balb/c mice were treated with LPS, cardiac function was measured by echocardiogaphy, and mitochondrial morphology determined by electron microscopy (EM). Drp1/Fis1 interaction was inhibited by P110 to determine whether limiting mitochondrial fission can reduce LPS-induced oxidative stress and cardiac dysfunction.LPS-treated H9C2 cardiomyocytes demonstrated a decrease in mitochondrial respiration followed by an increase in mitochondrial oxidative stress and a reduction in membrane potential. Inhibition of Drp1/Fis1 interaction with P110 attenuated LPS-mediated cellular oxidative stress and preserved membrane potential. In vivo, cardiac dysfunction in LPS-treated mice was associated with increased mitochondrial fragmentation. Treatment with P110 reduced cardiac mitochondrial fragmentation, prevented decline in cardiac function, and reduced mortality.Sepsis decreases cardiac mitochondrial respiration and membrane potential while increasing oxidative stress and inducing pathologic fission. Treatment with P110 was protective in both in vitro and in vivo models of septic cardiomyopathy, suggesting a key role of Drp1/Fis1 interaction, and a potential target to reduce its morbidity and mortality.

    View details for PubMedID 30981733

  • Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nature immunology Minhas, P. S., Liu, L., Moon, P. K., Joshi, A. U., Dove, C., Mhatre, S., Contrepois, K., Wang, Q., Lee, B. A., Coronado, M., Bernstein, D., Snyder, M. P., Migaud, M., Majeti, R., Mochly-Rosen, D., Rabinowitz, J. D., Andreasson, K. I. 2018


    Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD+ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD+ synthesis by limiting the conversion of downstream quinolinate to NAD+, a profile recapitulated in aging macrophages. Increasing de novo NAD+ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD+ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD+ synthesis may underlie declining NAD+ levels and rising innate immune dysfunction in aging and age-associated diseases.

    View details for PubMedID 30478397

  • Mortal engines: Mitochondrial bioenergetics and dysfunction in neurodegenerative diseases. Pharmacological research Joshi, A. U., Mochly-Rosen, D. 2018


    Mitochondria are best known for their role in ATP generation. However, studies over the past two decades have shown that mitochondria do much more than that. Mitochondria regulate both necrotic and apoptotic cell death pathways, they store and therefore coordinate cellular Ca2+ signaling, they generate and metabolize important building blocks, by-products and signaling molecules, and they also generate and are targets of free radical species that modulate many aspects of cell physiology and pathology. Most estimates suggest that although the brain makes up only 2% percent of body weight, utilizes about 20 percent of the body's total ATP. Thus, mitochondrial dysfunction greatly impacts brain functions and is indeed associated with numerous neurodegenerative diseases. Furthermore, a number of abnormal disease-associated proteins have been shown to interact directly with mitochondria, leading to mitochondrial dysfunction and subsequent neuronal cell death. Here, we discuss the role of mitochondrial dynamics impairment in the pathological processes associated with neurodegeneration and suggest that a therapy targeting mitochondrial dysfunction holds a great promise.

    View details for PubMedID 30144530

  • Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington's disease. Journal of molecular and cellular cardiology Joshi, A. U., Ebert, A. E., Haileselassie, B., Mochly-Rosen, D. 2018; 127: 125–33


    Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder, best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances, is caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). However, in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed in all tissues, impairs other organ systems. Not surprisingly, cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with HD. Mitochondrial dysfunction in the brain and skeletal muscle in HD has been well documented, as the disease progresses. However, not much is known about mitochondrial abnormalities in the heart. In this study, we describe a role for Drp1/Fis1-mediated excessive mitochondrial fission and dysfunction, associated with lysosomal dysfunction in H9C2 expressing long polyglutamine repeat (Q73) and in human iPSC-derived cardiomyocytes transfected with Q77. Expression of long polyglutamine repeat led to reduced ATP production and mitochondrial fragmentation. We observed an increased accumulation of damaged mitochondria in the lysosome that was coupled with lysosomal dysfunction. Importantly, reducing Drp1/Fis1-mediated mitochondrial damage significantly improved mitochondrial function and cell survival. Finally, reducing Fis1-mediated Drp1 recruitment to the mitochondria, using the selective inhibitor of this interaction, P110, improved mitochondrial structure in the cardiac tissue of R6/2 mice. We suggest that drugs focusing on the central nervous system will not address mitochondrial function across all organs, and therefore will not be a sufficient strategy to treat or slow down HD disease progression.

    View details for DOI 10.1016/j.yjmcc.2018.12.004

    View details for PubMedID 30550751

  • Inhibition of Drp1/Fis1 interaction slows progression of amyotrophic lateral sclerosis. EMBO molecular medicine Joshi, A. U., Saw, N. L., Vogel, H., Cunnigham, A. D., Shamloo, M., Mochly-Rosen, D. 2018


    Bioenergetic failure and oxidative stress are common pathological hallmarks of amyotrophic lateral sclerosis (ALS), but whether these could be targeted effectively for novel therapeutic intervention needs to be determined. One of the reported contributors to ALS pathology is mitochondrial dysfunction associated with excessive mitochondrial fission and fragmentation, which is predominantly mediated by Drp1 hyperactivation. Here, we determined whether inhibition of excessive fission by inhibiting Drp1/Fis1 interaction affects disease progression. We observed mitochondrial excessive fragmentation and dysfunction in several familial forms of ALS patient-derived fibroblasts as well as in cultured motor neurons expressing SOD1 mutant. In both cell models, inhibition of Drp1/Fis1 interaction by a selective peptide inhibitor, P110, led to a significant reduction in reactive oxygen species levels, and to improvement in mitochondrial structure and functions. Sustained treatment of mice expressing G93A SOD1 mutation with P110, beginning at the onset of disease symptoms at day 90, produced an improvement in motor performance and survival, suggesting that Drp1 hyperactivation may be an attractive target in the treatment of ALS patients.

    View details for PubMedID 29335339

  • Drp1/Fis1 interaction mediates mitochondrial dysfunction, bioenergetic failure and cognitive decline in Alzheimer's disease. Oncotarget Joshi, A. U., Saw, N. L., Shamloo, M., Mochly-Rosen, D. 2018; 9 (5): 6128–43


    Mitochondrial dynamics, involving a balance between fusion and fission, regulates mitochondrial quality and number. Increasing evidence suggests that dysfunctional mitochondria play a role in Alzheimer's disease (AD). We observed that Drp1 interaction with one of the adaptors, Fis1, is significantly increased in Aβ-treated neurons and AD patient-derived fibroblasts. P110, a seven-amino acid peptide, which specifically inhibits Drp1/Fis1 interaction without affecting the interaction of Drp1 with its other adaptors, attenuated Aβ42-induced mitochondrial recruitment of Drp1 and prevented mitochondrial structural and functional dysfunction in cultured neurons, in cells expressing mutant amyloid precursor protein (KM670/671NL), and in five different AD patient-derived fibroblasts. Importantly, sustained P110 treatment significantly improved behavioral deficits, and reduced Aβ accumulation, energetic failure and oxidative stress in the brain of the AD mouse model, 5XFAD. This suggests that Drp1/Fis1 interaction and excessive mitochondrial fission greatly contribute to Aβ-mediated and AD-related neuropathology and cognitive decline. Therefore, inhibiting excessive Drp1/Fis1-mediated mitochondrial fission may benefit AD patients.

    View details for PubMedID 29464060

  • The Role of Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) in Neuropathology and Neurodegeneration. Acta neurologica Taiwanica Chen, C., Joshi, A. U., Mochly-Rosen, D. 2016; 25(4): 111-123


    Aldehydes-induced toxicity has been implicated in many neurodegenerative diseases. Exposure to reactive aldehydes from (1) alcohol and food metabolism; (2) environmental pollutants, including car, factory exhausts, smog, pesticides, herbicides; (3) metabolism of neurotransmitters, amino acids and (4) lipid peroxidation of biological membrane from excessive ROS, all contribute to 'aldehydic load' that has been linked to the pathology of neurodegenerative diseases. In particular, the α, β-unsaturated aldehydes derived from lipid peroxidation, 4-hydroxynonenal (4-HNE), DOPAL (MAO product of dopamine), malondialdehyde, acrolein and acetaldehyde, all readily form chemical adductions with proteins, DNA and lipids, thus causing neurotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH 2) is a major aldehyde metabolizing enzyme that protects against deleterious aldehyde buildup in brain, a tissue that has a particularly high mitochondrial content. In this review, we highlight the deleterious effects of increased aldehydic load in the neuropathology of ischemic stroke, Alzheimer's disease and Parkinson's disease. We also discuss evidence for the association between ALDH2 deficiency, a common East Asianspecific mutation, and these neuropathologies. A novel class of small molecule aldehyde dehydrogenase activators (Aldas), represented by Alda-1, reduces neuronal cell death in models of ischemic stroke, Alzheimer's disease and Parkinson's disease. Together, these data suggest that reducing aldeydic load by enhancing the activity of aldehyde dehydrogenases, such as ALDH2, represents as a therapeutic strategy for neurodegenerative diseases.

    View details for PubMedID 28382610

  • Potential biomarkers to follow the progression and treatment response of Huntington's disease. journal of experimental medicine Disatnik, M., Joshi, A. U., Saw, N. L., Shamloo, M., Leavitt, B. R., Qi, X., Mochly-Rosen, D. 2016


    Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

    View details for PubMedID 27821553

  • The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained. Cell calcium Joshi, A. U., Kornfeld, O. S., Mochly-Rosen, D. 2016; 60 (3): 218-234


    Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca(2+) transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases.

    View details for DOI 10.1016/j.ceca.2016.04.010

    View details for PubMedID 27212603

  • Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Protein-Protein Interaction Inhibitor Reveals a Non-catalytic Role for GAPDH Oligomerization in Cell Death JOURNAL OF BIOLOGICAL CHEMISTRY Qvit, N., Joshi, A. U., Cunningham, A. D., Ferreira, J. C., Mochly-Rosen, D. 2016; 291 (26): 13608-13621


    Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an important glycolytic enzyme, has a non-catalytic (thus a non-canonical) role in inducing mitochondrial elimination under oxidative stress. We recently demonstrated that phosphorylation of GAPDH by delta protein kinase C (PKC) inhibits this GAPDH-dependent mitochondrial elimination. deltaPKC phosphorylation of GAPDH correlates with increased cell injury following oxidative stress, suggesting that inhibiting GAPDH phosphorylation should decrease cell injury. Using rational design, we identified pseudoGAPDH peptide, an inhibitor of deltaPKC-mediated GAPDH phosphorylation that does not inhibit the phosphorylation of other deltaPKC substrates. Unexpectedly, pseudoGAPDH decreased mitochondrial elimination and increased cardiac damage in an animal model of heart attack. Either treatment with pseudoGAPDH or direct phosphorylation of GAPDH by deltaPKC decreased GAPDH tetramerization, which corresponded to reduced GAPDH glycolytic activity in vitro and ex vivo. Taken together, our study identified the potential mechanism by which oxidative stress inhibits the protective GAPDH-mediated elimination of damaged mitochondria. Our study also identified a pharmacological tool, pseudoGAPDH peptide, with interesting properties. pseudoGAPDH peptide is an inhibitor of the interaction between deltaPKC and GAPDH, and of the resulting phosphorylation of GAPDH by deltaPKC. pseudoGAPDH peptide is also an inhibitor of GAPDH oligomerization and thus an inhibitor of GAPDH glycolytic activity. Finally, we found that pseudoGAPDH peptide is an inhibitor of the elimination of damaged mitochondria. We discuss how this unique property of increasing cell damage following oxidative stress suggests a potential use for pseudoGAPDH peptide-based therapy.

    View details for DOI 10.1074/jbc.M115.711630

    View details for PubMedID 27129213

  • VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease. Nature communications Guo, X., Sun, X., Hu, D., Wang, Y., Fujioka, H., Vyas, R., Chakrapani, S., Joshi, A. U., Luo, Y., Mochly-Rosen, D., Qi, X. 2016; 7: 12646-?


    Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.

    View details for DOI 10.1038/ncomms12646

    View details for PubMedID 27561680

  • Deficiency of Factor VII activating protease alters the outcome of ischemic stroke in mice EUROPEAN JOURNAL OF NEUROSCIENCE Joshi, A. U., Orset, C., Engelhardt, B., Baumgart-Vogt, E., Gerriets, T., Vivien, D., Kanse, S. M. 2015; 41 (7): 963-973

    View details for DOI 10.1111/ejn.12830

    View details for Web of Science ID 000352540800010

  • Plasma factor VII-activating protease antigen levels and activity are increased in ischemic stroke. Journal of thrombosis and haemostasis : JTH Hanson, E., Kanse, S. M., Joshi, A., Jood, K., Nilsson, S., Blomstrand, C., Jern, C. 2012; 10 (5): 848–56


    Factor VII-activating protease (FSAP) is a recently discovered plasma protease with a role in the regulation of hemostasis and vascular remodeling processes. Higher levels and activity of FSAP have been reported in patients with deep vein thrombosis, but there are no data on plasma FSAP in ischemic stroke (IS).To investigate whether FSAP antigen levels and activity are associated with IS and/or etiologic subtypes of IS.To assess the potential association between FSAP and IS, plasma FSAP antigen levels and activity were measured in 600 consecutive IS patients and 600 population-based controls from the case-control study the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Blood sampling was performed in the acute phase and 3 months after the index stroke. FSAP was also investigated at the genetic level by genotyping of 33 single-nucleotide polymorphisms.Increased FSAP antigen level and activity, at both time-points, were independently associated with IS. Subtype analysis revealed similar associations for both FSAP measures, at both time-points, in all main IS subtypes. FSAP genotypes showed association with both FSAP plasma measurements, but not with IS.Increased plasma FSAP antigen levels and activity were associated with IS and all main etiologic subtypes, suggesting a possible role for FSAP in the pathophysiology of IS, irrespective of the underlying etiology.

    View details for DOI 10.1111/j.1538-7836.2012.04692.x

    View details for PubMedID 22409238

  • Murine aldo-keto reductase family 1 subfamily B: identification of AKR1B8 as an ortholog of human AKR1B10. Biological chemistry Joshi, A., Rajput, S., Wang, C., Ma, J., Cao, D. 2010; 391 (12): 1371–78


    Aldo-keto reductase family 1 member B10 (AKR1B10), over-expressed in multiple human cancers, might be implicated in cancer development and progression via detoxifying cytotoxic carbonyls and regulating fatty acid synthesis. In the present study, we investigated the ortholog of AKR1B10 in mice, an ideal modeling organism greatly contributing to human disease investigations. In the mouse, there are three aldo-keto reductase family 1 subfamily B (AKR1B) members, i.e., AKR1B3, AKR1B7, and AKR1B8. Among them, AKR1B8 has the highest similarity to human AKR1B10 in terms of amino acid sequence, computer-modeled structures, substrate spectra and specificity, and tissue distribution. More importantly, similar to human AKR1B10, mouse AKR1B8 associates with murine acetyl-CoA carboxylase-α and mediates fatty acid synthesis in colon cancer cells. Taken together, our data suggest that murine AKR1B8 is the ortholog of human AKR1B10.

    View details for DOI 10.1515/BC.2010.144

    View details for PubMedID 21087085

  • TGF-beta signaling, tumor microenvironment and tumor progression: the butterfly effect. Frontiers in bioscience (Landmark edition) Joshi, A., Cao, D. 2010; 15: 180–94


    Transforming growth factor-beta (TGF-beta) signals through receptor serine/threonine kinases and intracellular Smad effectors, regulating numerous epithelial cell processes. TGF-beta plays a crucial role in the cancer initiation and progression through tumor cell autonomous signaling and interactions with tumor microenvironment, but is featured with a butterfly effect upon the stages of tumorigenesis. TGF-beta signaling acts as a suppressor of epithelial cell tumorigenesis at early stages, but promotes tumor progression by enhancing migration, invasion, and survival of the tumor cells during the later stages. TGF-beta signaling also cross-talks with other cell survival signaling pathways. Tumor microenvironment contains many distinct cell types, which substantially influences the tumor cell growth and survival, and the invasion and metastasis. TGF-beta in the microenvironment, produced by cancer and/or stromal cells, is high and negatively correlates with disease progression and patient prognosis. Therefore, TGF-beta may affect tumor progression by multiple mechanisms in addition to its direct action on tumor cells, and the diversities of TGF-beta signaling in tumors imply a need for caution to TGF-beta-targeted strategies of tumor prevention and/or therapeutics.

    View details for PubMedID 20036814