Publications
Thioredoxin and aging: What have we learned from the survival studies?.
Madeline G Roman, Lisa C Flores, Geneva M Cunningham, Christie Cheng, Colton Allen, Gene B Hubbard, Yidong Bai, Thomas L Saunders, Yuji Ikeno
Aging Pathobiol Ther. 2020;2(3):126-133. doi: 10.31491/apt.2020.09.028.
Abstract:
Our laboratory has conducted the first systematic survival studies to examine the biological effects of the antioxidant protein thioredoxin (Trx) on aging and age-related pathology. Our studies with C57BL/6 mice overexpressing Trx1 [Tg(act-TRX1)+/0 and Tg(TXN)+/0) demonstrated a slight extension in early lifespan compared to wild-type (WT) mice; however, no significant effects were observed in the later part of life. Overexpression of Trx2 in male C57BL/6 mice [Tg(TXN2)+/0] demonstrated a slightly extended lifespan compared to WT mice. The pathology results from two lines of Trx1 transgenic mice showed a slightly higher incidence of age-related neoplastic diseases compared to WT mice, and a slight increase in the severity of lymphoma, a major neoplastic disease, was observed in Trx2 transgenic mice. Together these studies indicate that Trx overexpression in one compartment of the cell (cytosol or mitochondria alone) has marginal beneficial effects on lifespan. On the other hand, down-regulation of Trx in either the cytosol (Trx1KO) or mitochondria (Trx2KO) showed no significant changes in lifespan compared to WT mice, despite several changes in pathophysiology of these knockout mice. When we examined the synergetic effects of overexpressing Trx1 and Trx2, TXNTg x TXN2Tg mice showed a significantly shorter lifespan with accelerated cancer development compared to WT mice. These results suggest that synergetic effects of Trx overexpression in both the cytosol and mitochondria on aging are deleterious and the development of age-related cancer is accelerated. On the other hand, we have recently found that down-regulation of Trx in both the cytosol and mitochondria in Trx1KO x Trx2KO mice has beneficial effects on aging. The results generated from our lab along with our ongoing study using Trx1KO x Trx2KO mice could elucidate the key pathways (i.e., apoptosis and autophagy) that prevent accumulation of damaged cells and genomic instability leading to reduced cancer formation.
Keywords: Thioredoxin; aging; cancer; knockout mouse; lifespan; transgenic mouse.
Joint modelling of longitudinal and survival data in the presence of competing risks with applications to prostate cancer data
Md Tuhin Sheikh, Joseph G Ibrahim, Jonathan A Gelfond, Wei Sun, Ming-Hui Chen
Stat Modelling. 2021 Feb;21(1-2):72-94. doi: 10.1177/1471082X20944620. Epub 2020 Sep 25.
Abstract:
This research is motivated from the data from a large Selenium and Vitamin E Cancer Prevention Trial (SELECT). The prostate specific antigens (PSAs) were collected longitudinally, and the survival endpoint was the time to low-grade cancer or the time to high-grade cancer (competing risks). In this article, the goal is to model the longitudinal PSA data and the time-to-prostate cancer (PC) due to low- or high-grade. We consider the low-grade and high-grade as two competing causes of developing PC. A joint model for simultaneously analysing longitudinal and time-to-event data in the presence of multiple causes of failure (or competing risk) is proposed within the Bayesian framework. The proposed model allows for handling the missing causes of failure in the SELECT data and implementing an efficient Markov chain Monte Carlo sampling algorithm to sample from the posterior distribution via a novel reparameterization technique. Bayesian criteria, ΔDICSurv, and ΔWAICSurv, are introduced to quantify the gain in fit in the survival sub-model due to the inclusion of longitudinal data. A simulation study is conducted to examine the empirical performance of the posterior estimates as well as ΔDICSurv and ΔWAICSurv and a detailed analysis of the SELECT data is also carried out to further demonstrate the proposed methodology.
Keywords: DIC; SELECT data; WAIC; cause-specific competing risks model; mixed effects model; reparametrization.
Leptin Receptors in RIP-Cre25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice
Ashish Singha, Juan Pablo Palavicini, Meixia Pan, Scotlynn Farmer, Darleen Sandoval, Xianlin Han, Teppei Fujikawa
Front Endocrinol (Lausanne). 2020 Sep 23:11:588447. doi: 10.3389/fendo.2020.588447. eCollection 2020.
Abstract:
Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.
Keywords: glucose metabolism; insulin deficiency; leptin; lipid metabolism; the hypothalamus.
Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism
Chih-Wei Chou, Xi Tan, Chia-Nung Hung, Brandon Lieberman, Meizhen Chen, Meena Kusi, Kohzoh Mitsuya, Chun-Lin Lin, Masahiro Morita, Zhijie Liu, Chun-Liang Chen, Tim Hui-Ming Huang
Cancers (Basel). 2020 Sep 22;12(9):2715. doi: 10.3390/cancers12092715.
Abstract:
The interplay between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is central to maintain energy homeostasis. It remains to be determined whether there is a mechanism governing metabolic fluxes based on substrate availability in microenvironments. Here we show that menin is a key transcription factor regulating the expression of OXPHOS and glycolytic genes in cancer cells and primary tumors with poor prognosis. A group of menin-associated proteins (MAPs), including KMT2A, MED12, WAPL, and GATA3, is found to restrain menin’s full function in this transcription regulation. shRNA knockdowns of menin and MAPs result in reduced ATP production with proportional alterations of cellular energy generated through glycolysis and OXPHOS. When shRNA knockdown cells are exposed to metabolic stress, the dual functionality can clearly be distinguished among these metabolic regulators. A MAP can negatively counteract the regulatory mode of menin for OXPHOS while the same protein positively influences glycolysis. A close-proximity interaction between menin and MAPs allows transcriptional regulation for metabolic adjustment. This coordinate regulation by menin and MAPs is necessary for cells to rapidly adapt to fluctuating microenvironments and to maintain essential metabolic functions.
Keywords: circulating tumor cells; glycolysis; menin; menin-associated proteins; oxidative phosphorylation.
Docosahexaenoic Acid (DHA) Supplementation Alters Phospholipid Species and Lipid Peroxidation Products in Adult Mouse Brain, Heart, and Plasma
Grace Y Sun, Michael K Appenteng, Runting Li, Taeseon Woo, Bo Yang, Chao Qin, Meixia Pan, Magdalena Cieślik, Jiankun Cui, Kevin L Fritsche, Zezong Gu, Matthew Will, David Beversdorf, Agata Adamczyk, Xianlin Han, C Michael Greenlief
Neuromolecular Med. 2021 Mar;23(1):118-129. doi: 10.1007/s12017-020-08616-0. Epub 2020 Sep 14.
Abstract:
The abundance of docosahexaenoic acid (DHA) in phospholipids in the brain and retina has generated interest to search for its role in mediating neurological functions. Besides the source of many oxylipins with pro-resolving properties, DHA also undergoes peroxidation, producing 4-hydroxyhexenal (4-HHE), although its function remains elusive. Despite wide dietary consumption, whether supplementation of DHA may alter the peroxidation products and their relationship to phospholipid species in brain and other body organs have not been explored sufficiently. In this study, adult mice were administered a control or DHA-enriched diet for 3 weeks, and phospholipid species and peroxidation products were examined in brain, heart, and plasma. Results demonstrated that this dietary regimen increased (n-3) and decreased (n-6) species to different extent in all major phospholipid classes (PC, dPE, PE-pl, PI and PS) examined. Besides changes in phospholipid species, DHA-enriched diet also showed substantial increases in 4-HHE in brain, heart, and plasma. Among different brain regions, the hippocampus responded to the DHA-enriched diet showing significant increase in 4-HHE. Considering the pro- and anti-inflammatory pathways mediated by the (n-6) and (n-3) polyunsaturated fatty acids, unveiling the ability for DHA-enriched diet to alter phospholipid species and lipid peroxidation products in the brain and in different body organs may be an important step forward towards understanding the mechanism(s) for this (n-3) fatty acid on health and diseases.
Keywords: Docosahexaenoic acid; Heart; Hippocampus; Lipid peroxidation; Lipidomics; Plasma.
A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin
Jamie N Justice, Sriram Gubbi, Ameya S Kulkarni, Jenna M Bartley, George A Kuchel, Nir Barzilai
Geroscience. 2021 Jun;43(3):1093-1112. doi: 10.1007/s11357-020-00261-6. Epub 2020 Sep 9.
Abstract:
We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
Keywords: Aging; COVID-19; Geroscience; Immunity; Metformin.
Analysis of monohexosyl alkyl (alkenyl)-acyl glycerol in brain samples by shotgun lipidomics
Chunyan Wang, Jianing Wang, Chao Qin, Xianlin Han
Anal Chim Acta. 2020 Sep 8:1129:143-149. doi: 10.1016/j.aca.2020.07.016. Epub 2020 Jul 24.
Abstract:
Lipid species possess very different structures, leading to their very diversified cellular functions in biological systems. Lipidomics represents a powerful technology for deep analysis of hundreds to thousands of intact lipid molecular species. In the current study, a cluster of unknown ion peaks was displayed when we profiled cerebroside species in rat spinal cord samples by neutral loss scan of 162 Da in the positive ion mode using a multi-dimensional mass spectrometry-based shotgun lipidomics strategy. In order to identify the structural identities of these unknown ion peaks, MS2 and MS3 analyses of these ions were performed by high mass resolution mass spectrometry. Extensive lines of evidence allowed us to identify that these unknown ion peaks were monohexosyl alkyl-acyl glycerol (HAAG) species, including their sn-positional isomers and alkyl-acyl compositional isomers. We also applied the developed method to identify and quantify HAAG species present in a variety of mouse nerve tissues. We believe that the first kind of lipidomics study on HAAG species present in mammalian nerve tissue samples provided the foundation for future biological research in this unknown area.
Keywords: Glycolipids; Lipids; Mass spectrometry; Monohexosyl alkyl-acyl glycerol; Neurodegeneration; Shotgun lipidomics.
The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats
Mitchell E Allen, Edward Ross Pennington, Justin B Perry, Sahil Dadoo, Marina Makrecka-Kuka, Maija Dambrova, Fatiha Moukdar, Hetal D Patel, Xianlin Han, Grahame K Kidd, Emily K Benson, Tristan B Raisch, Steven Poelzing, David A Brown, Saame Raza Shaikh
Commun Biol. 2020 Jul 17;3(1):389. doi: 10.1038/s42003-020-1101-3.
Abstract:
Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.
Pathogenic Tau Causes a Toxic Depletion of Nuclear Calcium.
Rebekah Mahoney, Elizabeth Ochoa Thomas, Paulino Ramirez, Henry E Miller, Adrian Beckmann, Gabrielle Zuniga, Radek Dobrowolski, Bess Frost.
Cell Reports. 2020 Jul 14;32(2):107900. doi: 10.1016/j.celrep.2020.107900.
Abstract:
Synaptic activity-induced calcium (Ca2+) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer’s disease and related tauopathies, on nuclear Ca2+. We find that pathogenic tau depletes nuclear Ca2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila, and that activation of big potassium (BK) channels elevates nuclear Ca2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer’s disease.
Epigenomics-based identification of oestrogen-regulated long noncoding RNAs in ER+ breast cancer
Zhao Zhang, Wei Yu, Dan Tang, Yufan Zhou, Mingjun Bi, Hu Wang, Yan Zheng, Mingqiu Chen, Li Li, Xinping Xu, Wei Zhang, Huimin Tao, Victor X Jin, Zhijie Liu, Lizhen Chen
RNA Biol. 2020 Nov;17(11):1590-1602. doi: 10.1080/15476286.2020.1777769. Epub 2020 Jun 18.
Abstract:
Breast cancer is one of the most prevalent cancers in women worldwide. Through the regulation of many coding and non-coding target genes, oestrogen (E2 or 17β-oestradiol) and its nuclear receptor ERα play important roles in breast cancer development and progression. Despite the astounding advances in our understanding of oestrogen-regulated coding genes over the past decades, our knowledge on oestrogen-regulated non-coding targets has just begun to expand. Here we leverage epigenomic approaches to systematically analyse oestrogen-regulated long non-coding RNAs (lncRNAs). Similar to the coding targets of ERα, the transcription of oestrogen-regulated lncRNAs correlates with the activation status of ERα enhancers, measured by eRNA production, chromatin accessibility, and the occupancy of the enhancer regulatory components including P300, MED1, and ARID1B. Our 3D chromatin architecture analyses suggest that lncRNAs and their neighbouring E2-resonsive coding genes, exemplified by LINC00160 and RUNX1, might be regulated as a 3D structural unit resulted from enhancer-promoter interactions. Finally, we evaluated the expression levels of LINC00160 and RUNX1 in various types of breast cancer and found that their expression positively correlated with the survival rate in ER+ breast cancer patients, implying that the oestrogen-regulated LINC00160 and its neighbouring RUNX1 might represent potential biomarkers for ER+ breast cancers.
Keywords: Epigenomics-basedidentification; breast cancer; long noncoding RNA; oestrogen.