News Article | March 2, 2017
(Philadelphia, PA) - Mitochondria - the energy-generating powerhouses of cells - are also a site for oxidative stress and cellular calcium regulation. The latter two functions have long been suspected of being linked mechanistically, and now new research at the Lewis Katz School of Medicine at Temple University (LKSOM) shows precisely how, with the common connection centering on a protein complex known as the mitochondrial Ca2+ uniporter (MCU). "MCU had been known for its part in driving mitochondrial calcium uptake for cellular energy production, which protects cells from bioenergetic crisis, and for its role in eliciting calcium overload-induced cell death," explained senior investigator on the study, Muniswamy Madesh, PhD, Professor in the Department of Medical Genetics and Molecular Biochemistry and Center for Translational Medicine at LKSOM. "Now, we show that MCU has a functional role in both calcium regulation and the sensing of levels of reactive oxygen species (ROS) within mitochondria." The study, published online March 2 in the journal Molecular Cell, is the first to identify a direct role for MCU in mitochondrial ROS-sensing. In previous work, Dr. Madesh and colleagues were the first to show how the MCU protein complex comes together to effect mitochondrial calcium uptake. "We know from that work, and from existing work in the field, that as calcium accumulates in mitochondria, the organelles generate increasing amounts of ROS," Dr. Madesh said. "Mitochondria have a way of dealing with that ROS surge, and because of the relationship between mitochondrial calcium uptake and ROS production, we suspected ROS-targeting of MCU was involved in that process." In the new study, Dr. Madesh and colleagues employed advanced biochemical, cell biological, and superresolution imaging to examine MCU oxidation in the mitochondrion. Critically, they discovered that MCU contains several cysteine molecules in its amino acid structure, only one of which, Cys-97, is capable of undergoing an oxidation-induced reaction known as S-glutathionylation. Structural analyses showed that oxidation-induced S-glutathionylation of Cys-97 triggers conformational changes within MCU. Those changes in turn regulate MCU activity during inflammation, hypoxia, and cardiac stimulation. They also appear to be relevant to cell survival - elimination of ROS-sensing via Cys-97 mutation resulted in persistent MCU channel activity and an increased rate of calcium-uptake, with cells eventually dying from calcium overload. Importantly, Dr. Madesh and colleagues found that S-glutathionylation of Cys-97 is reversible. "Reversible oxidation is essential to the regulation of protein function," Dr. Madesh explained. When switched on by oxidation, Cys-97 augments MCU channel activity that perpetuates cell death. Oxidation reverses when the threat has subsided. The findings could have implications for the understanding of metabolic disorders and neurological and cardiovascular diseases. "Abnormalities in ion homeostasis are a central feature of metabolic disease," Dr. Madesh said. "We plan next to explore the functional significance of ROS and MCU activity in a mouse model using genome editing technology, which should help us answer fundamental questions about MCU's biological functions in mitochondrial ROS-sensing." Other researchers involved in the study include Zhiwei Dong, Santhanam Shanmughapriya, Dhanendra Tomar, Neeharika Nemani, Sarah L. Breves, Aparna Tripathi, Palaniappan Palaniappan, Massimo F. Riitano, Alison Worth, Ajay Seelam, Edmund Carvalho, Ramasamy Subbiah, Fabia?n Jan?a, and Sudarsan Rajan, Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine at LKSOM; Jonathan Soboloff, Department of Medical Genetics and Molecular Biochemistry at LKSOM; Xueqian Zhang and Joseph Y. Cheung, Center for Translational Medicine at LKSOM; Naveed Siddiqui and Peter B. Stathopulos, Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Solomon Lynch and Jeffrey Caplan, Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware; Suresh K. Joseph, MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia; Yizhi Peng and Zhiwei Dong, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. The research was supported in part by National Institutes of Health grants R01GM109882, R01HL086699, R01HL119306, 1S10RR027327, P01 DA037830, and RO1DK103558. Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University. The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation. Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.
News Article | October 6, 2016
Using a mouse model of multiple sclerosis (MS), a research team led by UC San Francisco scientists has demonstrated for the first time that regenerating myelin – the fatty insulating sheath surrounding neural fibers that is destroyed in the disorder – can both protect neurons from damage and restore lost function. “The key thing we learned from this study is that if we can design therapies that promote remyelination – especially when myelin has been damaged by inflammation as it is in MS – we can prevent neuronal loss and restore function,” said UCSF’s Jonah R. Chan, Ph.D., the senior author of the new study, which was published September 27, 2016 in the open-access journal eLife. “This is something I and other investigators have wanted to promise to MS patients, but we simply didn’t have the data.” In MS, the immune system somehow goes awry and attacks myelin, compromising the efficient transmission of electrical impulses among brain cells. This leads to a range of progressively worsening symptoms, including vision problems, numbness, weakness, and difficulty walking. There is increasing evidence that, in addition to its insulating properties, myelin also provides metabolic support to axons, the wire-like nerve-cell extensions it ensheathes. In MS, as myelin continually degrades, axons also degenerate, ultimately causing nerve cells to die off completely. It is this degeneration that is thought to be responsible for the chronic disability and progression of symptoms seen in MS. In light of this disease process, it would seem logical that restoring myelin would protect axons, which in turn would protect neurons overall and help to maintain normal brain function, and many scientists and pharmaceutical firms are pursuing MS treatments based on just that premise. But Chan, the Debbie and Andy Rachleff Distinguished Professor of Neurology at UCSF, said he was frankly surprised to learn that there were no hard data to support this key hypothesis, and he therefore assembled an international team of scientists to conduct the new study. The researchers used the so-called EAE (experimental autoimmune encephalomyelitis) model of MS, in which mice are injected with a protein found in myelin, which incites an inflammatory autoimmune response with physiological and behavioral consequences similar to those seen in human MS. In previous UCSF research employing high-throughput drug-screening technology that Chan designed, he and colleagues discovered a cluster of compounds, all of which target proteins known as muscarinic receptors, that promote remyelination – the process by which cells known as oligodendrocytes will rewrap themselves around axons to repair the myelin sheath. Within this collection was an over-the-counter antihistamine called clemastine. In the current study, the researchers simultaneously injected mice with both clemastine and the protein that induces EAE, and they indeed found that these mice had less severe MS-like symptoms, and that some remyelination took place in the brain and spinal cord. Axons also appeared to be protected from degeneration in mice that received clemastine. But clemastine’s mechanism of action is poorly understood, Chan said, and pharmacologically speaking it is a “dirty” compound: in addition to its effects on histamine and muscarinic receptors, it interacts with many other types of receptors, and it affects many types of cells besides oligodendrocytes. So it wasn’t possible for the researchers to disentangle whether the less-severe symptoms and evidence of new myelin seen in clemastine-treated mice were truly the direct result of a specific effect of the drug on oligodendrocytes, or was instead due to some broader, indirect effect, such as dampening the overall inflammatory response. To address this question, the team conducted a series of experiments to identify which oligodendrocyte receptor clemastine might be acting on. They obtained numerous “knockout” mice, each lacking a specific receptor target, and systematically tested the drugs identified in the previous high-throughput screen in these mice. Ultimately, the team identified M1R (muscarinic acetylcholine receptor 1 subtype) as the target for clemastine and other anti-muscarinic compounds identified in the original screen, and determined that M1R was a potent inhibitor of oligodendrocyte differentiation from precursor cells, which is critical for remyelination. No drugs exist that specifically and potently block M1 without affecting other muscarinic receptors, so the group continued using a genetic approach, employing knockout mice lacking the M1 receptor specifically in oligodendrocytes and testing these mice in the EAE model of MS. In these mice, there was significant remyelination, axons were protected from degeneration, and function was restored, even when EAE inflammation was at its peak. Because of the precision of the gene knockout, the researchers are confident that all these effects followed from the absence of the M1 receptor in oligodendrocytes, which appears to have a profound inhibitory effect on remyelination. The next step, Chan said, will be to try to design a “first-in-class” M1-blocking drug and to test its efficacy in animal models, and ultimately in MS patients. To that end, Chan and co-author Ari J. Green, M.D., associate professor of neurology and clinical director of the UCSF Multiple Sclerosis Center, have partnered with Daniel Lorrain, Ph.D., head of biology, and Brian Stearns, Ph.D., head of chemistry, at San Diego-based Inception Sciences to advance this project. They were joined by researchers from the Third Military Medical University; Inception Sciences; the University of Vermont; the National Institutes of Health (NIH); and Texas Tech University Health Sciences Center. The work was funded by the National Multiple Sclerosis Society; Target ALS; The National Institutes of Health; and the Rachleff Endowment. “Now that we’ve shown we can promote repair during the peak inflammation period, and that new myelin may remain stable,” Chan said, “we can now say to MS patients that focusing on this remyelination space has the potential to not only restore function, but to improve their quality of life.”
Li, Third Military Medical University, Meditech and Chongqing Qingyang Pharmaceutical Co. | Date: 2011-05-18
Provided are a series of Gq protein competitive inhibitory polypeptides (GCIPs), polynucleotides encoding them, and preparation methods thereof. Also provided are pharmaceutical compositions comprising GCIP polypeptides and their uses in the manufacture of drugs for treating myocardial hypertrophy.
Tianjin Chasesun Pharmaceutical Co. and Third Military Medical University | Date: 2011-03-21
The use of Kukoamine A and Kukoamine B in the preparation of drugs for the prevention and treatment of sepsis and autoimmune disease is disclosed. Bacterial endotoxin/lipopolysaccaride (LPS) and unmethylated DNA (CpG DNA) of bacteria, the major pathogen-associated molecular patterns in sepsis and autoimmune disease, are specifically targeted, while the disclosed use directionally isolates lead compounds from traditional Chinese medicine. These measures can overcome the major defects of uncertainty of pharmacological material basis and drug targets of extracts and constituents of traditional Chinese medicine. The disclosed use can help in developing a safe, effective and quality controllable drug for prevention and treatment of sepsis and autoimmune disease so as to help solve the present lack of effective drugs in clinical treatment.
Third Military Medical University and Tianjin Chasesun Pharmaceutical Co. | Date: 2013-09-18
Provided are salts of kukoamine B, their preparation method and their use in preventing and treating sepsis diseases.
Third Military Medical University and Tianjin Chasesun Pharmaceutical Co. | Date: 2013-05-15
Use of kukoamine A and kukoamine B in preparing medicine for preventing and treating sepsis and autoimmune diseases. The kukoamine A and kukoamine B are extracted from cortex lycii radicis. The medicine is used for antagonism of bacterial endotoxin (LPS) and bacteria non-methylated DNA (CpG DNA).
Yoshikai N.,Nanyang Technological University |
Wei Y.,Third Military Medical University
Asian Journal of Organic Chemistry | Year: 2013
Pyrroles, indoles, and carbazoles are among the most important families of nitrogen-containing heterocycles that occur frequently in natural products, pharmaceuticals, agrochemicals, and other functional molecules. Consequently, improved syntheses of these compounds continue to interest synthetic chemists. This Focus Review describes recent advances in synthetic methods for producing these privileged heterocycles that feature transition-metal-catalyzed C-H activation approaches. Because of the common five-membered pyrrole core, some of the C-H activation approaches are applicable to two or more of the pyrrole, indole, and carbazole skeletons. The reactions discussed here not only serve as atom- and step-economical alternatives to the existing synthetic methods, but also show the latest developments in organometallic chemistry and homogeneous catalysis. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Huang S.G.,Third Military Medical University
PloS one | Year: 2013
Glioma pathogenesis related-2 (GLIPR-2) belongs to pathogenesis related-1 (PR-1) family whose function remains unknown. In our previous studies, GLIPR-2 was found to be a novel potent stimulator of epithelial-to-mesenchymal transition (EMT) in renal fibrosis which has been classified as type 2 EMT. However, whether GLIPR-2 could induce type 3 EMT in carcinogenesis needs further investigation. In this study, we showed that GLIPR-2 was expressed in hepatocellular carcinoma (HCC) tissues, hypoxia could upregulate the expression of GLIPR-2 in HepG2 and PLC/PRF/5 cells in vitro, overexpression of this protein promoted migration and invasion via EMT, knockdown of GLIPR-2 attenuated migration and invasion of HepG2 and PLC/PRF/5 cells in hypoxia. Moreover, extracellular signal-regulated kinases 1 and 2 (ERK1/2) are positively regulated by GLIPR-2. Taken together, we provide evidence for a hypoxia/GLIPR-2/EMT/migration and invasion axis in HCC cells and it provides novel insights into the mechanism of migration and invasion of hepatocellular carcinoma cells in hypoxia condition.
Olymvax Biopharmaceuticals Inc. and Third Military Medical University | Date: 2013-12-09
Provided is staphylococcus protein A expressed by a mutational Staphylococcus aureus and its coding sequence, as well as a vector, host bacteria, composition or kit which contains the coding sequence of the mutational protein. Also provided is the use of the mutational protein and the composition thereof in the preparation of vaccines, therapeutic antibodies, diagnostic kits and the like, and for the prevention, treatment and detection of infections by Staphylococcus aureus. Also provided are methods for producing, fermenting and purifying the mutational protein.
Third Military Medical University | Date: 2014-06-27
The invention discloses application of irisin in the preparation of drugs for preventing myocardial ischemia reperfusion injuries. Experimental results show that irisin can decrease the myocardial infarction area caused by ischemia reperfusion, reduce the increase of the contents of lactate dehydrogenase (LDH), troponin (cTnI), creatine kinase (CK), and other myocardial enzyme markers caused by ischemia reperfusion, meanwhile reducing the inflammatory response, myocardial apoptosis, and oxidative stress response caused by myocardial ischemia reperfusion, promote peroxysome proliferator-activated receptor nuclear translocation, and inhibit nuclear transcription factor NF-B nuclear translocation and accordingly decrease myocardial structure injuries and load increase caused by ischemia reperfusion. Therefore, irisin can be used for preventing and decreasing myocardial reperfusion injuries and has important clinical significance on the treatment of myocardial ischemia.