Health science Center in Shreveport

Shreveport, LA, United States

Health science Center in Shreveport

Shreveport, LA, United States
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Sreedhar A.,Health science Center in Shreveport | Zhao Y.,Health science Center in Shreveport
Mitochondrion | Year: 2017

Mitochondria are fascinating organelles involved in various cellular-metabolic activities that are integral for mammalian development. Although they perform diverse, yet interconnected functions, mitochondria are remarkably regulated by complex signaling networks. Therefore, it is not surprising that mitochondrial dysfunction is involved in plethora of diseases, including neurodegenerative and metabolic disorders. One of the many factors that lead to mitochondrial-associated metabolic diseases is the uncoupling protein-2, a family of mitochondrial anion proteins present in the inner mitochondrial membrane. Since their discovery, uncoupling proteins have attracted considerable attention due to their involvement in mitochondrial-mediated oxidative stress and energy metabolism.This review attempts to provide a summary of recent developments in the field of uncoupling protein 2 relating to mitochondrial associated metabolic diseases. © 2017 Elsevier B.V. and Mitochondria Research Society.


Xue S.Y.,Health science Center in Shreveport | Hebert V.Y.,Health science Center in Shreveport | Hayes D.M.,Health science Center in Shreveport | Robinson C.N.,Health science Center in Shreveport | And 2 more authors.
Toxicological Sciences | Year: 2013

Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTIs of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial cytotoxicity, in some cases, cells were cotreated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6 h, NRTIs increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/ NADH ratio. Moreover, nitric oxide levels were decreased, whereas endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTIs only, markers for mitochondrial toxicity returned to baseline levels by 18-24 h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and Nix, respectively, we observed autophagy of mitochondria at 8-10 h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTIinduced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction. © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Glover M.,Health science Center in Shreveport | Hebert V.Y.,Health science Center in Shreveport | Nichols K.,Health science Center in Shreveport | Xue S.Y.,Health science Center in Shreveport | And 3 more authors.
Antiviral Research | Year: 2014

Nucleoside reverse transcriptase inhibitors (NRTIs) are considered the backbone of current combination therapies for HIV. These therapies have significantly decreased mortality and morbidity in HIV-infected patients, but some are associated with cardiovascular complications, including endothelial dysfunction, an early marker for atherosclerosis. Our prior studies demonstrated that co-treatment of cells with an antioxidant therapy reversed NRTI-induced endothelial injury. Thus, as a proof of concept that mitochondrially-targeted antioxidants may be useful in preventing NRTI toxicity, in the current study, mice overexpressing a mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), were compared with wild-type (WT) mice. Mice were treated chronically with either zidovudine (AZT), lamivudine (3TC), or tenofovir (TDF) to determine whether overexpression of MnSOD protected them from endothelial dysfunction. Endothelial function was assessed using vessel reactivity experiments on thoracic aortas as well as measures of endothelium derived factors nitric oxide (NO), endothelin-1 (ET-1), and prostacyclin. Oxidative stress was evaluated as levels of plasma 8-isoprostane. Alterations in vessel reactivity, NO, and ET-1 in WT mice treated with AZT or 3TC were noted. Overexpression of MnSOD offered protection from decreases in vessel reactivity and increases in ET-1. These findings indicate that mitochondrial oxidative stress induced by AZT or 3TC plays a major role in mediating NRTI-induced endothelial dysfunction, and suggest that the use of targeted antioxidants administered in conjunction with NRTIs may attenuate these effects. © 2014 Published by Elsevier B.V.


Li W.,Health science Center in Shreveport | Li W.,Hebei University | Nichols K.,Health science Center in Shreveport | Nathan C.-A.,Health science Center in Shreveport | Zhao Y.,Health science Center in Shreveport
Cancer Biomarkers | Year: 2013

BACKGROUND: Mitochondrial uncoupling protein 2 (UCP2) uncouples electron transport from ATP production. UCP2 has been shown to play an important role in obesity and diabetes. Interestingly, studies have demonstrated that UCP2 is up-regulated in human colon cancer samples. OBJECTIVE: In order to study the role of UCP2 in human cancers, we detected the UCP2 protein level in various human tumor tissues. METHODS: Six types of human tumor and adjacent normal tissue samples were collected and analyzed by Western blot assays to detect the levels of UCP2. RESULTS: The results showed that in the human head and neck, skin, prostate, and pancreatic tumor samples examined, the protein levels of UCP2 were significantly higher in tumor tissues than that in the adjacent normal tissues. The protein levels of UCP2 was lower in non-small cell lung tumor tissues, which is marginal significant. CONCLUSIONS: Over expression of UCP2 in certain tumors provides the rationale to speculate that UCP2 may promote tumor growth in these cancers. © 2013 - IOS Press and the authors. All rights reserved.


Li W.,Health science Center in Shreveport | Li W.,Hebei University | Liu J.,Health science Center in Shreveport | Jackson K.,Health science Center in Shreveport | And 2 more authors.
PLoS ONE | Year: 2014

Shikonin, a small-molecule natural product which inhibits the activity of pyruvate kinase M2 (PKM2), has been studied as an anti-cancer drug candidate in human cancer models. Here, our results demonstrate that shikonin is able to sensitize human breast cancer cells to chemotherapy by paclitaxel (taxol). Human breast adenocarcinoma MBA-MD-231 cells, which have higher levels of PKM2 expression and activity compared with MCF-7 cells, were selected to study further. The concentrations of shikonin and taxol were first selected at which they did not significantly induce cytotoxicity when treated alone, whereas the combination induced apoptosis. Surprisingly, PKM2 activity was decreased by shikonin, but not by the combination treatment. To identify the potential targets of this combination, human phospho-kinase antibody array analysis was performed and results indicated that the combination treatment inhibited the activation of ERK, Akt, and p70S6 kinases, which are known to contribute to breast cancer progression. Finally, how the combination affects breast cancer cell growth in vivo was tested using a xenograft tumor model. The results indicated that shikonin plus taxol prolonged animal survival and reduced tumor size than the vehicle treatment group. In summary, our results suggest that shikonin has a potential as an adjuvant for breast cancer therapy. © 2014 Li et al.


Li W.,Health science Center in Shreveport | Liu J.,Caddo Parish Magnet High School | Zhao Y.,Health science Center in Shreveport
Molecular Carcinogenesis | Year: 2014

Chemoprevention has been a pivotal and effective strategy during the skin cancer treatment. Using human skin normal and tumor samples, we demonstrated that both the expression and activity levels of pyruvate kinase M2 (PKM2) were higher in skin tumor tissues than normal tissues, suggesting that PKM2, one of important metabolic enzyme, might serve as a target for skin cancer prevention and/or therapy. Shikonin, a small-molecule active chemical, has been studied as an anti-cancer drug candidate in human cancer models. However, the mechanism of action and the chemopreventive potential of shikonin are unclear. Herein, we used the skin epidermal JB6 P+ cells and demonstrated that shikonin suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) induced neoplastic cell transformation and PKM2 activation in the early stage of carcinogenesis. Mitochondrial functions were inhibited by TPA treatment, as indicated by reduced mitochondrial membrane potential and mitochondrial respiration, which were restored by shikonin. We also examined the levels of lactate as a glycolysis marker, and shikonin suppressed its increase caused by tumor promoter treatment. Modulation of cell metabolism by shikonin was associated with G2-M phase accumulation, and Fra-1 (a major subunit of activator protein 1 in skin tumorigenesis) downregulation. In addition, we demonstrated that AMP-activated protein kinase (AMPK), an energy sensor, which is inactivated by TPA, shikonin could reverse AMPK activity. These results suggest that shikonin bears chemopreventive potential for human skin cancers in which PKM2 is upregulated, which might be mediated by inhibiting oncogenic activation, PKM2 activation, and mitochondrial dysfunction. © 2012 Wiley Periodicals, Inc.


Wang F.,Health science Center in Shreveport | Wang F.,Jilin University | Liu J.,Health science Center in Shreveport | Robbins D.,Health science Center in Shreveport | And 4 more authors.
Apoptosis | Year: 2011

Increasing evidence has shown that a fraction of the wild-type (wt) form of the tumor suppressor p53, can translocate to mitochondria due to genotoxic stress. The mitochondrial targets of wt p53 have also been studied. However, whether mutant p53, which exists in 50% of human cancers, translocates to mitochondria and affects mitochondrial functions is unclear. In this study, we used doxorubicin, a chemotherapeutic drug, to treat five human lymphoma cell lines with wt, mutant or deficient in p53, to induce p53 activation and mitochondrial translocation. Our results demonstrated that mutant p53, like wt p53, was induced upon doxorubicin treatment. Similarly, a fraction of mutant p53 also translocated to mitochondria. However, Complex I and II activities in the mitochondria were compromised only in wt p53-bearing cells after doxorubicin treatment, but not in mutant p53-bearing cells. Similarly, doxorubicin treatment caused greater cell death only in wt p53-bearing cells, but not in mutant p53-bearing cells. When p53 deficient Ramos cells were transfected with mutant p53 (249S), the cells showed resistance to doxorubicin-induced cell death and decreases in complex activities. To reactivate mutant p53 and reverse chemoresistance, ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) was used to treat mutant p53 cells. Ellipticine enhanced p53 mitochondrial translocation, decreased Complex I activity, and sensitized p53 mutant cells to doxorubicin-induced apoptosis. In summary, our studies suggest that mutations in p53 may not hinder p53's mitochondrial translocation, but impair its effects on mitochondrial functions. Therefore, restoring mutant p53 by ellipticine may sensitize these cells to chemotherapy. © 2010 Springer Science+Business Media, LLC.


Wang F.,Health science Center in Shreveport | Wang F.,Jilin University | Fu X.,Jilin University | Chen X.,Jilin University | And 2 more authors.
PLoS ONE | Year: 2010

The tumor suppressor p53 is known to be able to trigger apoptosis in response to DNA damage, oncogene activation, and certain chemotherapeutic drugs. In addition to its transcriptional activation, a fraction of p53 translocates to mitochondria at the very early stage of apoptosis, which eventually contributes to the loss of mitochondrial membrane potential, generation of reactive oxygen species (ROS), cytochrome c release, and caspase activation. However, the mitochondrial events that affect p53 translocation are still unclear. Since mitochondrial uncoupling has been suggested to contribute to cancer development, herein, we studied whether p53 mitochondrial translocation and subsequent apoptosis were affected by mitochondrial uncoupling using chemical protonophores, and further verified the results using a siRNA approach in murine skin epidermal JB6 cells. Our results showed that mitochondrial uncoupling blocked p53 mitochondrial translocation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA), a known tumor promoter to induce p53-mediated apoptosis in skin carcinogenesis. This blocking effect, in turn, led to preservation of mitochondrial functions, and eventually suppression of caspase activity and apoptosis. Moreover, uncoupling protein 2 (UCP2), a potential suppressor of ROS in mitochondria, is important for TPA-induced cell transformation in JB6 cells. UCP2 knock down cells showed enhanced p53 mitochondrial translocation, and were less prone to form colonies in soft agar after TPA treatment. Altogether, our data suggest that mitochondrial uncoupling may serve as an important regulator of p53 mitochondrial translocation and p53-mediated apoptosis during early tumor promotion. Therefore, targeting mitochondrial uncoupling may be considered as a novel treatment strategy for cancer. © 2010 Wang et al.


Singleterry J.,Health science Center in Shreveport | Sreedhar A.,Health science Center in Shreveport | Zhao Y.,Health science Center in Shreveport
Mitochondrion | Year: 2014

All forms of life share a common indispensible need of energy. The requirement of energy is necessary for an organism not only to survive but also to thrive. The metabolic activities in normal cells rely predominately on mitochondrial oxidative phophorylation for energy generation in the form of ATP. On the contrary, cancer cells predominately rely on glycolysis rather than oxidative phosphorylation. It is long believed that an impairment of mitochondrial oxidative phosphorylation is the cause of this glycolytic phenotype observed in cancers. However, studies in cancer metabolism have revealed that mitochondrial function in many cancers is intact. It has also been observed that cancers utilize various forms of metabolism. The various metabolic phenotypes that are employed by cancer cells have a common purpose, to balance macromolecular biosynthesis and sufficient ATP production in order to support the rapid proliferation rate characteristic of these aberrant cells. These metabolic pathways are attractive targets for possible therapeutic interventions and currently research is underway to meet this end. More importantly, normal cells have essentially the same metabolic requirements as cancer cells so finding an approach to target these metabolic pathways without incurring detrimental effects on normal tissues remains the challenge. © 2014 Elsevier B.V. and Mitochondria Research Society.


Withaferin A (WA) is a bioactive compound derived from Withania somnifera. The antitumor activity of WA has been well studied in human cancer models; however, its chemopreventive potential is unclear. In the present study, we used the skin epidermal JB6 P+ cells, a well-established model for tumor promotion, and demonstrated that WA suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell transformation and cell proliferation. Interestingly, TPA inactivated isocitrate dehydrogenase 1 (IDH1), which was reversed by WA. Similar results were also observed in mouse skin tissue. Therefore, we focused on metabolism as the potential mechanism of action. We found that mitochondrial functions were downregulated by TPA treatment, as indicated by reduced mitochondrial membrane potential, complex I activity and mitochondrial respiration. However, all of these downregulations were inhibited by WA. In addition, we examined the levels of α-ketoglutarate, a product of IDH1, and WA blocked its reduction upon TPA treatment. Finally, we detected the lactate level as a glycolysis marker, and WA suppressed its elevation caused by tumor promoter treatment. Altogether, these results suggest that WA might exert its chemopreventive activity via inhibiting not only oncogenic activation, but also IDH1 inactivation and mitochondrial dysfunction in early tumorigenesis. © 2012 Japanese Cancer Association.

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