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News Article | April 20, 2017
Site: www.chromatographytechniques.com

Spermidine—a compound found in foods like aged cheese, mushrooms, soy products, legumes, corn and whole grains—seems to prevent (at least in animal models) liver fibrosis and hepatocellular carcinoma, which is the most common type of liver cancer. There is also some evidence that it may prolong lifespan, according to a study published recently in the journal Cancer Research. Researchers gave animal models an oral supplement of spermidine and found that they lived longer and were less likely than untreated individuals to have liver fibrosis and cancerous liver tumors, even when predisposed for those conditions. “It’s a dramatic increase in lifespan of animal models, as much as 25 percent,” said Leyuan Liu, assistant professor at the Texas A&M Institute of Biosciences and Technology’s Center for Translational Cancer Research. “In human terms, that would mean that instead of living to about 81 years old, the average American could live to be over 100.” The trouble is that people would need to begin ingesting spermidine from the time they begin eating solid food to get this kind of significant improvement in their lifespans; those animal models treated later only saw a 10 percent increase in longevity. Still, it may be the most sustainable option scientists have found yet. “Only three interventions—severely cutting the number of calories consumed, restricting the amount of methionine (a type of amino acid found in meat and other proteins) in the diet and using the drug rapamycin—have been shown to truly prolong the lifespans of vertebrates, but eating less and not eating meat will not be welcomed by general population, while rapamycin has shown to suppress the human immune system,” Liu said. “Therefore, spermidine may be a better approach.” Long-term spermidine ingestion might be possible for humans if it can be eventually made into a supplement and shown to be safe. Liu is optimistic that this might be the case. “Spermidine is a product naturally found in food, so we hope it would have minimal side effects,” he said. “The next steps would be human clinical trials to determine safety and efficacy.” Spermidine is a type of compound called a polyamine and was first isolated from semen, which explains its name. It likely works to prevent cancer by enhancing MAP1S-activated autophagy, or the cells’ self-eating behavior: The benefits of spermidine disappear when MAP1S isn’t available. This builds off Liu’s earlier work, which indicated that autophagy—or the lack thereof—plays a role in cancer and premature aging. Damaged cells due to defective autophagy can go on to replicate and become tumors or cause other problems. Spermidine can prevent this process. There is also some evidence that it might improve cardiovascular health. Even if people didn’t begin taking spermidine until later in life, they still might be able to get these liver and heart benefits. The animal models exposed to spermidine showed reductions in both liver lesions and intensity of liver fibrosis, a condition that often leads to liver cancer. Liu has a novel idea about how to incorporate the compound, similar to how folic acid has been added to most grain products to prevent neural tube defects. “Just think: if we added spermidine to every bottle of beer, it might balance out the alcohol and help protect the liver,” he said. Still, Liu urges caution, as these results are preliminary and only—as of now—in animal models. “It’s still early,” he said, “but perhaps one day this approach will provide a novel strategy to prolong lifespans, prevent or reverse liver fibrosis and prevent, delay or cure hepatocellular carcinoma in humans.”


News Article | April 20, 2017
Site: www.chromatographytechniques.com

Spermidine—a compound found in foods like aged cheese, mushrooms, soy products, legumes, corn and whole grains—seems to prevent (at least in animal models) liver fibrosis and hepatocellular carcinoma, which is the most common type of liver cancer. There is also some evidence that it may prolong lifespan, according to a study published recently in the journal Cancer Research. Researchers gave animal models an oral supplement of spermidine and found that they lived longer and were less likely than untreated individuals to have liver fibrosis and cancerous liver tumors, even when predisposed for those conditions. “It’s a dramatic increase in lifespan of animal models, as much as 25 percent,” said Leyuan Liu, assistant professor at the Texas A&M Institute of Biosciences and Technology’s Center for Translational Cancer Research. “In human terms, that would mean that instead of living to about 81 years old, the average American could live to be over 100.” The trouble is that people would need to begin ingesting spermidine from the time they begin eating solid food to get this kind of significant improvement in their lifespans; those animal models treated later only saw a 10 percent increase in longevity. Still, it may be the most sustainable option scientists have found yet. “Only three interventions—severely cutting the number of calories consumed, restricting the amount of methionine (a type of amino acid found in meat and other proteins) in the diet and using the drug rapamycin—have been shown to truly prolong the lifespans of vertebrates, but eating less and not eating meat will not be welcomed by general population, while rapamycin has shown to suppress the human immune system,” Liu said. “Therefore, spermidine may be a better approach.” Long-term spermidine ingestion might be possible for humans if it can be eventually made into a supplement and shown to be safe. Liu is optimistic that this might be the case. “Spermidine is a product naturally found in food, so we hope it would have minimal side effects,” he said. “The next steps would be human clinical trials to determine safety and efficacy.” Spermidine is a type of compound called a polyamine and was first isolated from semen, which explains its name. It likely works to prevent cancer by enhancing MAP1S-activated autophagy, or the cells’ self-eating behavior: The benefits of spermidine disappear when MAP1S isn’t available. This builds off Liu’s earlier work, which indicated that autophagy—or the lack thereof—plays a role in cancer and premature aging. Damaged cells due to defective autophagy can go on to replicate and become tumors or cause other problems. Spermidine can prevent this process. There is also some evidence that it might improve cardiovascular health. Even if people didn’t begin taking spermidine until later in life, they still might be able to get these liver and heart benefits. The animal models exposed to spermidine showed reductions in both liver lesions and intensity of liver fibrosis, a condition that often leads to liver cancer. Liu has a novel idea about how to incorporate the compound, similar to how folic acid has been added to most grain products to prevent neural tube defects. “Just think: if we added spermidine to every bottle of beer, it might balance out the alcohol and help protect the liver,” he said. Still, Liu urges caution, as these results are preliminary and only—as of now—in animal models. “It’s still early,” he said, “but perhaps one day this approach will provide a novel strategy to prolong lifespans, prevent or reverse liver fibrosis and prevent, delay or cure hepatocellular carcinoma in humans.”


Humtsoe J.O.,University of California at San Francisco | Liu M.,Institute of Biosciences and Technology | Malik A.B.,University of Illinois at Chicago | Wary K.K.,University of Illinois at Chicago
Molecular and Cellular Biology | Year: 2010

Endothelial cell (EC) migration, cell-cell adhesion, and the formation of branching point structures are considered hallmarks of angiogenesis; however, the underlying mechanisms of these processes are not well understood. Lipid phosphate phosphatase 3 (LPP3) is a recently described p120-catenin-associated integrin ligand localized in adherens junctions (AJs) of ECs. Here, we tested the hypothesis that LPP3 stimulates β-catenin/lymphoid enhancer binding factor 1 (β-catenin/LEF-1) to induce EC migration and formation of branching point structures. In subconfluent ECs, LPP3 induced expression of fibronectin via β-catenin/LEF-1 signaling in a phosphatase and tensin homologue (PTEN)-dependent manner. In confluent ECs, depletion of p120-catenin restored LPP3-mediated β-catenin/LEF-1 signaling. Depletion of LPP3 resulted in destabilization of β-catenin, which in turn reduced fibronectin synthesis and deposition, which resulted in inhibition of EC migration. Accordingly, reexpression of β-catenin but not p120-catenin in LPP3-depleted ECs restored de novo synthesis of fibronectin, which mediated EC migration and formation of branching point structures. In confluent ECs, however, a fraction of p120-catenin associated and colocalized with LPP3 at the plasma membrane, via the C-terminal cytoplasmic domain, thereby limiting the ability of LPP3 to stimulate β-catenin/LEF-1 signaling. Thus, our study identified a key role for LPP3 in orchestrating PTEN-mediated β-catenin/LEF-1 signaling in EC migration, cell-cell adhesion, and formation of branching point structures. Copyright © 2010, American Society for Microbiology.


Ichite N.,Florida A&M University | Chougule M.,University of Hawaii at Hilo | Patel A.R.,Florida A&M University | Jackson T.,Florida A&M University | And 3 more authors.
Molecular Cancer Therapeutics | Year: 2010

The purpose of this study was to determine the anticancer efficacy of 1,1-bis (3′-indolyl)-1-(p-biphenyl) methane (DIM-C-pPhC6H 5) by inhalation delivery alone and in combination with i.v. docetaxel in a murine model for lung cancer. An aqueous DIM-C-pPhC 6H5 formulation was characterized for its aerodynamic properties. Tumor-bearing athymic nude mice were exposed to nebulized DIM-C-pPhC6H5, docetaxel, or combination (DIM-C-pPhC 6H5 plus docetaxel) using a nose-only exposure technique. The aerodynamic properties included mass median aerodynamic diameter of 1.8 ± 0.3 μm and geometric SD of 2.31 ± 0.02. Lung weight reduction in mice treated with the drug combination was 64% compared with 40% and 47% in mice treated with DIM-C-pPhC6H5 aerosol and docetaxel alone, respectively. Combination treatment decreased expression of Akt, cyclin D1, survivin, Mcl-1, NF-κB, IκBα, phospho-IκBα, and vascular endothelial growth factor (VEGF) and increased expression of c-Jun NH2-terminal kinase 2 and Bad compared with tumors collected from single-agent treatment and control groups. DNA fragmentation was also enhanced in mice treated with the drug combination compared with docetaxel or DIM-C-pPhC6H5 alone. Combination treatment decreased expressions of VEGF and CD31 compared with single-agent treated and control groups. These results suggest that DIM-C-pPhC6H5 aerosol enhanced the anticancer activity of docetaxel in a lung cancer model by activating multiple signaling pathways. The study provides evidence that DIM-C-pPhC6H5 can be used alone or in combination with other drugs for the treatment of lung cancer using the inhalation delivery approach. ©2010 AACR.


Lu W.,University of Houston | Chen Z.,University of Houston | Chen Z.,University of Pennsylvania | Zhang H.,University of Houston | And 3 more authors.
Cell Death and Disease | Year: 2012

Mitochondrial respiratory dysfunction has intimate relationship with redox regulation. The key mechanism about how the mitochondrial respiration-defective cells survive oxidative stress is still elusive. Here, we report that transcription factor zincfinger protein 143 (ZNF143) expression and glutathione peroxidase (GPX) activity are markedly increased in the mitochondrial respiratory-defective cells induced by dominant-negative DNA polymerase γ (POLGdn). In this work, investigation of the cellular antioxidant glutathione (GSH) and enzyme GPX activity in the mitochondrial dysfunction revealed the presence of an increased synthesis of GSH through the activation of GCLC (glutamate-cysteine ligase catalytic subunit) and GCLM (glutamate-cysteine ligase regulatory subunit) gene expression, and also a positive upregulation of glutathione peroxidase 1 (GPX1) activity by the transcription factor ZNF143. Significant increase in gene expression of SepSecS, the key enzyme responsible for selenocysteine transfer RNA (tRNA) synthesis, further confirmed the activation of the selenocysteine synthesis pathway. By using both GPX1 and ZNF143 knockdown, we provided insight into the involvement of ZNF143 in promoting GPX1 activity and protecting cells from oxidative damage and cisplatin treatment in the mitochondrial dysfunction. Furthermore, we reported the possible regulation of mitochondrial transcription factor A (TFAM) in the mitochondrial dysfunction. Our findings delineate an important antioxidant survival pathway that allows the mitochondrial-defective cells to survive oxidative stress and cisplatin treatment. © 2012 Macmillan Publishers Limited.


Salojin K.V.,Lexicon Pharmaceuticals Inc. | Cabrera R.M.,Texas A&M University | Cabrera R.M.,University of Texas at Austin | Sun W.,Lexicon Pharmaceuticals Inc. | And 11 more authors.
Blood | Year: 2011

The human proton coupled folate transporter (PCFT) is involved in low pH-dependent intestinal folate transport. In this report, we describe a new murine model of the hereditary folate malabsorption syndrome that we developed through targeted disruption of the first 3 coding exons of the murine homolog of the PCFT gene. By 4 weeks of age, PCFT-deficient (PCFT-/-) mice developed severe macrocytic normochromic anemia and pancytopenia. Immature erythroblasts accumulated in the bone marrow and spleen of PCFT-/- mice and failed to differentiate further, showing an increased rate of apoptosis in intermediate erythroblasts and reduced release of reticulocytes. In response to the inefficient hematologic development, the serum of the PCFT-/- animals contained elevated concentrations of erythropoietin, soluble transferrin receptor (sCD71), and thrombopoietin. In vivo folate uptake experiments demonstrated a systemic folate deficiency caused by disruption of PCFT-mediated intestinal folate uptake, thus confirming in vivo a critical and nonredundant role of the PCFT protein in intestinal folate transport and erythropoiesis. The PCFT-deficient mouse serves as a model for the hereditary folate malabsorption syndrome and is the most accurate animal model of folate deficiency anemia described to date that closely captures the spectrum of pathology typical of this disease. © 2011 by The American Society of Hematology.


Moussa S.H.,Texas A&M University | Kuznetsov V.,Texas A&M University | Tran T.A.T.,University of Texas Southwestern Medical Center | Sacchettini J.C.,Texas A&M University | And 2 more authors.
Protein Science | Year: 2012

Genetic studies have established that lysis inhibition in bacteriophage T4 infections occurs when the RI antiholin inhibits the lethal hole-forming function of the T holin. The T-holin is composed of a single N-terminal transmembrane domain and a ∼20 kDa periplasmic domain. It accumulates harmlessly throughout the bacteriophage infection cycle until suddenly causing permeabilization of the inner membrane, thereby initiating lysis. The RI antiholin has a SAR domain that directs its secretion to the periplasm, where it can either be inactivated and degraded or be activated as a specific inhibitor of T. Previously, it was shown that the interaction of the soluble domains of these two proteins within the periplasm was necessary for lysis inhibition. We have purified and characterized the periplasmic domains of both T and RI. Both proteins were purified in a modified host that allows disulfide bond formation in the cytoplasm, due to the functional requirement of conserved disulfide bonds. Analytical centrifugation and circular dichroism spectroscopy showed that RI was monomeric and exhibited ∼80% alpha-helical content. In contrast, T exhibited a propensity to oligomerize and precipitate at high concentrations. Incubation of RI with T inhibits this aggregation and results in a complex of equimolar T and RI content. Although gel filtration analysis indicated a complex mass of 45 kDa, intermediate between the predicted 30 kDa heterodimer and 60 kDa heterotetramer, sedimentation velocity analysis indicated that the predominant species is the former. These results suggest that RI binding to T is necessary and sufficient for lysis inhibition. © 2012 The Protein Society.


Arockiasamy A.,Texas A&M University | Aggarwal A.,Texas A&M University | Savva C.G.,Texas A&M University | Holzenburg A.,Texas A&M University | And 2 more authors.
Protein Science | Year: 2011

In eukaryotes, calcium-binding proteins play a pivotal role in diverse cellular processes, and recent findings suggest similar roles for bacterial proteins at different stages in their life cycle. Here, we report the crystal structure of calcium dodecin, Rv0379, from Mycobacterium tuberculosis with a dodecameric oligomeric assembly and a unique calcium-binding motif. Structure and sequence analysis were used to identify orthologs of Rv0379 with different ligand-binding specificity. © 2011 The Protein Society.


Ochoa C.E.,University of Houston | Ochoa C.E.,Monterrey Institute of Technology | Mirabolfathinejad S.G.,University of Houston | Venado A.R.,Monterrey Institute of Technology | And 8 more authors.
Cancer Prevention Research | Year: 2011

Several epidemiologic studies have found that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer compared with smokers without COPD. We have shown a causal role for COPD-like airway inflammation in lung cancer promotion in the CCSPCre/LSL-K-rasG12D mouse model (CC-LR). In contrast, existing epidemiologic data do not suggest any definite association between allergic airway inflammation and lung cancer. To test this, CC-LR mice were sensitized to ovalbumin (OVA) and then challenged with an OVA aerosol weekly for 8 weeks. This resulted in eosinophilic lung inflammation associated with increased levels of T helper 2 cytokines and mucous metaplasia of airway epithelium, similar to what is seen in asthmatic patients. However, this type of inflammation did not result in a significant difference in lung surface tumor number (49 ± 9 in OVA vs. 52 ± 5 in control) in contrast to a 3.2-fold increase with COPD-like inflammation. Gene expression analysis of nontypeable Haemophilus influenzae (NTHi)-treated lungs showed upregulation of a different profile of inflammatory genes, including interleukin 6 (IL-6), compared with OVA-treated lungs. Therefore, to determine the causal role of cytokines that mediate COPD-like inflammation in lung carcinogenesis, we genetically ablated IL-6 in CC-LR mice. This not only inhibited intrinsic lung cancer development (1.7-fold) but also inhibited the promoting effect of extrinsic COPD-like airway inflammation (2.6-fold). We conclude that there is a clear specificity for the nature of inflammation in lung cancer promotion, and IL-6 has an essential role in lung cancer promotion. ©2010 AACR.


Xie R.,Institute of Biosciences and Technology | Nguyen S.,Institute of Biosciences and Technology | McKeehan K.,Institute of Biosciences and Technology | Wang F.,Institute of Biosciences and Technology | And 2 more authors.
Journal of Biological Chemistry | Year: 2011

The ubiquitously distributed MAP1S is a homologue of the exclusively neuronal distributed microtubule-associated protein 1A and 1B (MAP1A/B). They give rise to multiple isoforms through similar post-translational modification. Isoforms of MAP1S have been implicated in microtubule dynamics and mitotic abnormalities and mitotic cell death. Here we show that ablation of the Map1s gene in mice caused reduction in the B-cell CLL/lymphoma 2 or xL (Bcl-2/xL) and cyclin-dependent kinase inhibitor 1B (P27) protein levels, accumulation of defective mitochondria, and severe defects in response to nutritive stress, suggesting defects in autophagosomal biogenesis and clearance. Furthermore, MAP1S isoforms interacted with the autophagosome-associated light chain 3 of MAP1A/B (LC3), a homologue of yeast autophagy-related gene 8 (ATG8), and recruited it to stable microtubules in aMAP1Sand LC3 isoform-dependent mode. In addition, MAP1S interacted with mitochondrion-associated leucine-rich PPR-motif containing protein (LRPPRC) that interacts with the mitophagy initiator and Parkinson disease-related protein Parkin. The three-way interactions of MAP1S isoforms with LC3 and microtubules as well as the interaction of MAP1S with LRPPRC suggest that MAP1S isoforms may play positive roles in integration of autophagic components with microtubules and mitochondria in both autophagosomal biogenesis and degradation. For the first time, our results clarify roles of MAP1S in bridging microtubules and mitochondria with autophagic and mitophagic initiation, maturation, trafficking, and lysosomal clearance. Defects in the MAP1S-regulated autophagy may impact heart disease, cancers, neurodegenerative diseases, and a wide range of other diseases. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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