BBA - Molecular Basis of Disease (v.1863, #4)
Editorial Board (i).
Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2 by Yang Yang; Chongxi Fan; Bodong Wang; Zhiqiang Ma; Dongjin Wang; Bing Gong; Shouyin Di; Shuai Jiang; Yue Li; Tian Li; Zhi Yang; Erping Luo (827-837).
In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100 mM) decreased cellular viability after 24 h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10 μM for 24 h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10 μM for 2 h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10 μM for 2 h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.Display Omitted
Keywords: High glucose; Oxidative stress; Pterostilbene; Nuclear factor erythroid 2-related factor 2 signaling; Neuroprotection;
Regulation of protein kinase C-related kinase (PRK) signalling by the TPα and TPβ isoforms of the human thromboxane A2 receptor: Implications for thromboxane- and androgen- dependent neoplastic and epigenetic responses in prostate cancer by Aine G. O'Sullivan; Eamon P. Mulvaney; B. Therese Kinsella (838-856).
The prostanoid thromboxane (TX) A2 and its T Prostanoid receptor (the TP) are increasingly implicated in prostate cancer (PCa). Mechanistically, we recently discovered that both TPα and TPβ form functional signalling complexes with members of the protein kinase C-related kinase (PRK) family, AGC- kinases essential for the epigenetic regulation of androgen receptor (AR)-dependent transcription and promising therapeutic targets for treatment of castrate-resistant prostate cancer (CRPC). Critically, similar to androgens, activation of the PRKs through the TXA2/TP signalling axis induces phosphorylation of histone H3 at Thr11 (H3Thr11), a marker of androgen-induced chromatin remodelling and transcriptional activation, raising the possibility that TXA2-TP signalling can mimic and/or enhance AR-induced cellular changes even in the absence of circulating androgens such as in CRPC. Hence the aim of the current study was to investigate whether TXA2/TP-induced PRK activation can mimic and/or enhance AR-mediated cellular responses in the model androgen-responsive prostate adenocarcinoma LNCaP cell line. We reveal that TXA2/TP signalling can act as a neoplastic- and epigenetic-regulator, promoting and enhancing both AR-associated chromatin remodelling (H3Thr11 phosphorylation, WDR5 recruitment and acetylation of histone H4 at lysine 16) and AR-mediated transcriptional activation (e.g of the KLK3/prostate-specific antigen and TMPRSS2 genes) through mechanisms involving TPα/TPβ mediated-PRK1 and PRK2, but not PRK3, signalling complexes. Overall, these data demonstrate that TPα/TPβ can act as neoplastic and epigenetic regulators by mimicking and/or enhancing the actions of androgens within the prostate and provides further mechanistic insights into the role of the TXA2/TP signalling axis in PCa, including potentially in CRPC.
Keywords: Thromboxane; Receptor; Androgen; Prostate cancer; Protein kinase C-related kinase; Epigenetics;
IL-6 promotes M2 macrophage polarization by modulating purinergic signaling and regulates the lethal release of nitric oxide during Trypanosoma cruzi infection by Liliana M. Sanmarco; Nicolás E. Ponce; Laura M. Visconti; Natalia Eberhardt; Martin G. Theumer; Ángel R. Minguez; Maria P. Aoki (857-869).
The production of nitric oxide (NO) is a key defense mechanism against intracellular pathogens but it must be tightly controlled in order to avoid excessive detrimental oxidative stress. In this study we described a novel mechanism through which interleukin (IL)-6 mediates the regulation of NO release induced in response to Trypanosoma cruzi infection. Using a murine model of Chagas disease, we found that, in contrast to C57BL/6 wild type (WT) mice, IL-6-deficient (IL6KO) mice exhibited a dramatic increase in plasma NO levels concomitant with a significantly higher amount of circulating IL-1β and inflammatory monocytes. Studies on mouse macrophages and human monocytes, revealed that IL-6 decreased LPS-induced NO production but this effect was abrogated in the presence of anti-IL-1β and in macrophages deficient in the NLRP3 inflammasome. In accordance, while infected WT myocardium exhibited an early shift from microbicidal/M1 to anti-inflammatory/M2 macrophage phenotype, IL6KO cardiac tissue never displayed a dominant M2 macrophage profile that correlated with decreased expression of ATP metabolic machinery and a lower cardiac parasite burden. The deleterious effects of high NO production-induced oxidative stress were evidenced by enhanced cardiac malondialdehyde levels, myocardial cell death and mortality. The survival rate was improved by the treatment of IL-6-deficient mice with a NO production-specific inhibitor. Our data revealed that IL-6 regulates the excessive release of NO through IL-1β inhibition and determines the establishment of an M2 macrophage profile within infected heart tissue.Display Omitted
Keywords: CD39; CD73; Human monocytes; Innate immunity;
Induction of hypothyroidism during early postnatal stages triggers a decrease in cognitive performance by decreasing hippocampal synaptic plasticity by Paulina Salazar; Pedro Cisternas; Juan Francisco Codocedo; Nibaldo C. Inestrosa (870-883).
Thyroid hormones are vital in the control of multiple body functions, including the correct performance of the brain. Multiple diseases are associated with thyroid gland functioning, including hypothyroidism. To date, little is known regarding the effects of the establishment of this condition at a young age on brain function. Here, we evaluated the effect of hypothyroidism in an early postnatal stage in cognitive abilities with focus on the hippocampus. In our model, hypothyroidism was induced in young rats at 21 days of age using 0.05% 6-propyl-2-thiouracil (PTU) for 4 weeks reaching significantly lower levels of fT4 (control: 1.337 ng/dL ± 0.115, PTU: 0.050 ng/dL ± 0.001). Following the induction of hypothyroidism, several cognitive tasks were assessed to investigate the effects of hypothyroidism on cognition performance. We determined that hypothyroidism triggers a significant dysfunction in learning and memory processes observed in the Morris Water Maze were the latency times were higher in PTU rats (controls: 37 s; PTU: 57 s). The cognitive impairment was correlated with a reduction in hippocampal plasticity with respect to both long-term potentiation (LTP) (control: 1.45, PTU: 1.00) and depression (LTD) (control: 0.71, PTU: 1.01). Furthermore, a decrease in the rate of glucose utilization (control: 223 nmol ∗ mg of protein, PTU:148 nmol ∗ mg of protein) was observed, along with an increase in oxidative stress and a decrease in MAP2 marker in the hippocampus. Our findings suggest that the induction of hypothyroidism in a young rat model alters numerous functions at the level of the hippocampus.
Keywords: Hypothyroidism; Hippocampus; Cognitive performance; Glucose metabolism;
Cytoplasmic stress granules: Dynamic modulators of cell signaling and disease by Hicham Mahboubi; Ursula Stochaj (884-895).
Stress granule (SG) assembly is a conserved cellular strategy to minimize stress-related damage and promote cell survival. Beyond their fundamental role in the stress response, SGs have emerged as key players for human health. As such, SG assembly is associated with cancer, neurodegenerative disorders, ischemia, and virus infections. SGs and granule-related signaling circuits are therefore promising targets to improve therapeutic intervention for several diseases. This is clinically relevant, because pharmacological drugs can affect treatment outcome by modulating SG formation.As membraneless and highly dynamic compartments, SGs regulate translation, ribostasis and proteostasis. Moreover, they serve as signaling hubs that determine cell viability and stress recovery. Various compounds can modulate SG formation and dynamics. Rewiring cell signaling through SG manipulation thus represents a new strategy to control cell fate under various physiological and pathological conditions.
Keywords: Stress; Stress granules; Cancer; Neurodegeneration; Virus infection;
Profibrotic IHG-1 complexes with renal disease associated HSPA5 and TRAP1 in mitochondria by Una Bhreathnach; Brenda Griffin; Eoin Brennan; Leah Ewart; Debra Higgins; Madeline Murphy (896-906).
The highly conserved mitochondrial protein induced in high glucose-1 (IHG-1) functions to maintain mitochondrial quality and is associated with the development of fibrosis in diabetic nephropathy. Towards identifying novel approaches to treating diabetic kidney disease, IHG-1-protein-protein interactions were investigated using epitope-tagged immunoprecipitation analyses followed by mass spectrometry. Here we show that IHG-1 is solely expressed in mitochondria and localised to the inner mitochondrial membrane, the region where mitochondrial reactive oxygen species are generated. Chaperones HSPA5 and TRAP1 and cold shock protein YBX1 were identified as IHG-1 binding partners. All three proteins are important in the cellular response to oxidative stress and play important roles in mitochondrial transcription and DNA repair. Both redox imbalance and IHG-1 stimulate TGF-β signalling. IHG-1, HSPA5 and YBX1 all show increased expression in diabetic nephropathy, chronic kidney disease and in the Unilateral Ureteral Obstruction model of kidney fibrosis. Increased IHG-1 expression in UUO correlated with loss of TRAP1 expression. IHG-1 may target TRAP1 for degradation. When IHG-1 is no longer localised to mitochondria, it retains the ability to interact with the cold shock protein YBX1, facilitating anti-fibrotic actions in the nucleus. Targeting these proteins may offer alternative treatments for fibrotic kidney disease.
Keywords: IHG-1; Diabetic nephropathy; Mitochondria; Respiration; Oxidative stress; TRAP1; HSPA5; Unilateral Ureteral Obstruction; Chronic kidney disease;
Vitamin D in liver disease: Current evidence and potential directions by Harendran Elangovan; Sarinder Chahal; Jenny E. Gunton (907-916).
Consistent with its multifaceted nature, growing evidence links vitamin D with hepatic disease. In this review, we summarise the roles of vitamin D in different liver pathologies and explore the clinical utility of vitamin D-based treatments in hepatology. We find that the small number of clinical trials coupled with the profound heterogeneity of study protocols limits the strength of evidence needed to ascribe definite clinical value to the hormone in liver disease. Nevertheless, the experimental data is promising and further bench and bedside studies will likely define a clearer role in hepatic therapeutics.
The telomere-binding protein TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine by Wei-Ping Lee; Keng-Hsin Lan; Chung-Pin Li; Yee Chao; Ming-Chih Hou; Han-Chieh Lin; Shou-Dong Lee (917-928).
Gemcitabine and capecitabine are two effective anticancer agents against solid tumors. The pharmacological mechanisms have been known as incorporation into DNA and thereby inhibition of DNA synthesis. When used as metronomic chemotherapy, they may inhibit angiogenesis and induce immunity. In our previous study, we showed that low-dose gemcitabine caused telomere shortening by stabilizing TRF2 that was required for XPF-dependent telomere loss. In this report, we established a SKOV3.ip1 ascites cell model. Tumor-bearing mice were treated with low-dose gemcitabine (GEM) or capecitabine (CAP). Both GEM and CAP caused telomere shortening and increased expression of TRF2 with improved ascites in nude mice and decreased in vitro clonogenic activity. TRF2 knockdown altered telomeres to a shortened but new status that may evade XPF-dependent telomere loss and conferred resistance of SKOV3.ip1 ascites cells to low-dose GEM and CAP. Our study provides a new mechanism of metronomic chemotherapy i.e. TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.
Keywords: TRF2; Telomere; Metronomic chemotherapy;
Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology by Tulin O. Price; Nader Sheibani; Gul N. Shah (929-935).
Events responsible for cerebrovascular disease in diabetes are not fully understood. Pericyte loss is an early event that leads to endothelial cell death, microaneurysms, and cognitive impairment. A biochemical mechanism underlying pericyte loss is rapid respiration (oxidative metabolism of glucose). This escalation in respiration results from free influx of glucose into insulin-insensitive tissues in the face of high glucose levels in the blood. Rapid respiration generates superoxide, the precursor to all reactive oxygen species (ROS), and results in pericyte death. Respiration is regulated by carbonic anhydrases (CAs) VA and VB, the two isozymes expressed in mitochondria, and their pharmacologic inhibition with topiramate reduces respiration, ROS, and pericyte death.Topiramate inhibits both isozymes; therefore, in the earlier studies, their individual roles were not discerned. In a recent genetic study, we showed that mitochondrial CA VA plays a significant role in regulation of reactive oxygen species and pericyte death. The role of CA VB was not addressed.In this report, genetic knockdown and overexpression studies confirm that mitochondrial CA VA regulates respiration in pericytes, whereas mitochondrial CA VB does not contribute significantly. Identification of mitochondrial CA VA as a sole regulator of respiration provides a specific target to develop new drugs with fewer side effects that may be better tolerated and can protect the brain from diabetic injury. Since similar events occur in the capillary beds of other insulin-insensitive tissues such as the eye and kidney, these drugs may also slow the onset and progression of diabetic disease in these tissues.
Keywords: Apoptosis; Brain peicytes; Diabetes; Mitochondrial carbonic anhydrases; Reactive oxygen species;
ROCK1/p53/NOXA signaling mediates cardiomyocyte apoptosis in response to high glucose in vitro and vivo by Dongmei Su; Lina Guan; Qianqian Gao; Qian Li; Cuige Shi; Yi Liu; Lei Sun; Cailing Lu; Xu Ma; Jing Zhao (936-946).
Gestational diabetes mellitus is a risk factor for congenital heart defects; however, the molecular basis of the congenital heart anomalies remains obscure. Previous reports showed a positive correlation between abnormal cardiomyocyte apoptosis and ventricular wall thinness, one type of congenital heart anomaly. This work explored the expression pattern and molecular mechanism of the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) gene in cardiomyocyte apoptosis and genesis of ventricular wall thinness. In this report, we found a marked increase in the number of apoptotic cardiomyocytes in response to high glucose (HG) treatment. Moreover, up-regulation of ROCK1 expression observed in diabetic offspring compared with controls was potentially associated with cardiomyocyte apoptosis and the ventricular wall thinness. Further investigation showed that p53 and NOXA protein levels increased during ROCK1-meidated apoptosis in response to HG. In response to HG, whereby ROCK1 phosphorylated p53 at Ser15 to up-regulate its protein level. Furthermore, we found that p53 mediated the expression of NOXA during HG-induced apoptosis, and histone acetyltransferase p300 participated in this process. These findings reveal a novel regulatory mechanism of ROCK1/p53/NOXA signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.Display Omitted
Keywords: Gestational diabetes mellitus; Congenital heart defects; ROCK1; p53; NOXA; p300;
The Zn2+-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl− absorption, via basolateral KCC1, and reduces fluid loss by Laxmi Sunuwar; Hila Asraf; Mark Donowitz; Israel Sekler; Michal Hershfinkel (947-960).
Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn2+ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn2+ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn2+ and ZnR/GPR39 are both required for a beneficial effect of Zn2+ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl− transport, a critical factor in diarrhea, by upregulating K+/Cl− cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl− absorption pathway. Finally, inhibition of KCC-dependent Cl− transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn2+ acting via ZnR/GPR39 has a direct role in controlling Cl− absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.
Keywords: Zinc signaling; Zinc sensing receptor; ZnR/GPR39; Diarrhea; K+/Cl− cotransporter; KCC;
Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation by Michela Di Nottia; Arianna Montanari; Daniela Verrigni; Romina Oliva; Alessandra Torraco; Erika Fernandez-Vizarra; Daria Diodato; Teresa Rizza; Marzia Bianchi; Michela Catteruccia; Massimo Zeviani; Carlo Dionisi-Vici; Silvia Francisci; Enrico Bertini; Rosalba Carrozzo (961-967).
The mitochondrial Elongation Factor Tu (EF-Tu), encoded by the TUFM gene, is a highly conserved GTPase, which is part of the mitochondrial protein translation machinery. In its activated form it delivers the aminoacyl-tRNAs to the A site of the mitochondrial ribosome. We report here on a baby girl with severe infantile macrocystic leukodystrophy with micropolygyria and a combined defect of complexes I and IV in muscle biopsy, caused by a novel mutation identified in TUFM. Using human mutant cells and the yeast model, we demonstrate the pathological role of the novel variant. Moreover, results of a molecular modeling study suggest that the mutant is inactive in mitochondrial polypeptide chain elongation, probably as a consequence of its reduced ability to bind mitochondrial aa-tRNAs. Four patients have so far been described with mutations in TUFM, and, following the first description of the disease in a single patient, we describe similar clinical and neuroradiological features in an additional patient.
Keywords: TUFM; Mitochondrial translation; Leukodystrophy; OXPHOS defects;
Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice by Vlada V. Zakharova; Olga Yu. Pletjushkina; Ivan I. Galkin; Roman A. Zinovkin; Boris V. Chernyak; Dmitri V. Krysko; Claus Bachert; Olga Krysko; Vladimir P. Skulachev; Ekaterina N. Popova (968-977).
Mitochondrial dysfunctions occur in many diseases linked to the systemic inflammatory response syndrome (SIRS). Mild uncoupling of oxidative phosphorylation is known to rescue model animals from pathologies related to mitochondrial dysfunctions and overproduction of reactive oxygen species (ROS). To study the potential of SIRS therapy by uncoupling, we tested protonophore dinitrophenol (DNP) and a free fatty acid (FFA) anion carrier, lipophilic cation dodecyltriphenylphosphonium (C12TPP) in mice and in vitro models of SIRS. DNP and C12TPP prevented the body temperature drop and lethality in mice injected with high doses of a SIRS inducer, tumor necrosis factor (TNF). The mitochondria-targeted antioxidant plastoquinonyl decyltriphenylphosphonium (SkQ1) which also catalyzes FFA-dependent uncoupling revealed similar protective effects and downregulated expression of the NFκB-regulated genes (VCAM1, ICAM1, MCP1, and IL-6) involved in the inflammatory response of endothelium in aortas of the TNF-treated mice. In vitro mild uncoupling rescued from TNF-induced endothelial permeability, disassembly of cell contacts and VE-cadherin cleavage by the matrix metalloprotease 9 (ММР9). The uncouplers prevented TNF-induced expression of MMP9 via inhibition of NFκB signaling. Water-soluble antioxidant Trolox also prevented TNF-induced activation and permeability of endothelium in vitro via inhibition of NFκB signaling, suggesting that the protective action of the uncouplers is linked to their antioxidant potential.
Keywords: Endothelium; Mitochondria; Mild uncoupling of oxidative phosphorylation; Mitochondria-targeted antioxidant SkQ1;
Steroidogenic acute regulatory protein (StAR) overexpression attenuates HFD-induced hepatic steatosis and insulin resistance by Yanyan Qiu; Xianxian Sui; Yongkun Zhan; Chen Xu; Xiaobo Li; Yanxia Ning; Xiuling Zhi; Lianhua Yin (978-990).
Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology. Intracellular lipid accumulation is the first step in the development and progression of NAFLD. Steroidogenic acute regulatory protein (StAR) plays an important role in the synthesis of bile acid and intracellular lipid homeostasis and cholesterol metabolism. We hypothesize that StAR is involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. The hypothesis was identified using free fatty acid (FFA)-overloaded NAFLD in vitro model and high-fat diet (HFD)-induced NAFLD mouse model transfected by recombinant adenovirus encoding StAR (StAR). StAR expression was also examined in pathology samples of patients with fatty liver by immunohistochemical staining. We found that the expression level of StAR was reduced in the livers obtained from fatty liver patients and NAFLD mice. Additionally, StAR overexpression decreased the levels of hepatic lipids and maintained the hepatic glucose homeostasis due to the activation of farnesoid x receptor (FXR). StAR overexpression attenuated the impairment of insulin signaling in fatty liver. This protective role of StAR was owing to a reduction of intracellular diacylglycerol levels and the phosphorylation of PKCε. Furthermore, FXR inactivation reversed the observed beneficial effects of StAR. The present study revealed that StAR overexpression can reduce hepatic lipid accumulation, regulate glucose metabolism and attenuate insulin resistance through a mechanism involving the activation of FXR. Our study suggests that StAR may be a potential therapeutic target for NAFLD.Display Omitted
Keywords: Steroidogenic acute regulatory protein; Fatty liver; Insulin resistance; Farnesoid x receptor;
Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits by Gorka Gerenu; Eva Martisova; Hilda Ferrero; Miguel Carracedo; Tomi Rantamäki; Maria Javier Ramirez; Francisco Javier Gil-Bea (991-1001).
Brain-derived neurotrophic factor (BDNF) plays pivotal roles in neuronal function. The cleaved – mature – form of BDNF (mBDNF), predominantly expressed in adult brains, critically determines its effects. However, insufficient proteolytic processing under pathology may lead to the precursor form of BDNF (proBDNF) and thereby increased neuronal apoptosis and synaptic weakening. Previous findings in our lab showed that cognitive stimulation (CS) delayed memory decline in Tg2576 mouse model of Alzheimer's disease (AD), an effect that was tightly associated with augmented levels of mBDNF. In view of this association, the present study explored whether altered cleavage of BDNF could be involved in AD-related traits triggered by excessive amyloid-β (Aβ) pathology and whether this process could be therapeutically targeted. Aβ pathology, both in AD patient samples and experimental models, triggered the upregulation of plasminogen-activator inhibitor-1 (PAI-1) via JNK/c-Jun. This led to inhibition of plasmin-regulated conversion of mBDNF. Pharmacological inhibition of PAI-1 with PAI-039 sufficiently reverted Aβ-induced tau hyperphosphorylation and neurotoxicity. Chronic treatment of 15 old-month Tg2576 mice with oral administration of PAI-039 resulted in improved BDNF maturation and cognitive function without inducing significant changes in amyloid burden. In conclusion, upregulation of PAI-1 may be a critical mechanism underlying insufficient neurotrophic support and increased neurodegeneration associated with AD. Thus, targeting BDNF maturation through pharmacological inhibition of PAI-1 might become a potential treatment for AD.Display Omitted
Keywords: Neurotrophin; Plasminogen; Beta-amyloid; Tau hyperphosphorylation; Memory;
UCP2 up-regulation within the course of autoimmune encephalomyelitis correlates with T-lymphocyte activation by Alina Smorodchenko; Stephanie Schneider; Anne Rupprecht; Karoline Hilse; Soleman Sasgary; Ute Zeitz; Reinhold G. Erben; Elena E. Pohl (1002-1012).
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) associated with severe neurological disability. Reactive oxygen species (ROS) and mitochondrial dysfunction play a pivotal role in the pathogenesis of this disease. Several members of the mitochondrial uncoupling protein subfamily (UCP2–UCP5) were suggested to regulate ROS by diminishing the mitochondrial membrane potential and constitute therefore a promising pharmacological target for MS. To evaluate the role of different uncoupling proteins in neuroinflammation, we have investigated their expression patterns in murine brain and spinal cord (SC) during different stages of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. At mRNA and protein levels we found that only UCP2 is up-regulated in the SC, but not in brain. The increase in UCP2 expression was antigen-independent, reached its maximum between 14 and 21 days in both OVA and MOG immunized animals and correlated with an augmented number of CD3+ T-lymphocytes in SC parenchyma. The decrease in abundance of UCP4 was due to neuronal injury and was only detected in CNS of MOG-induced EAE animals. The results provide evidence that the involvement of mitochondrial UCP2 in CNS inflammation during EAE may be mainly explained by the invasion of activated T-lymphocytes. This conclusion coincides with our previous observation that UCP2 is up-regulated in activated and rapidly proliferating T-cells and participates in fast metabolic re-programming of cells during proliferation.
Keywords: Neuroinflammation; Mitochondrial uncoupling proteins; Central nervous system; Metabolic re-programming of cells; Cell proliferation; UCP4;
Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development by Seung-Ju Cho; Bok-Sik Cha; Ok-Seon Kwon; Jisun Lim; Dong-Myung Shin; Dong Wook Han; Tohru Ishitani; Eek-hoon Jho; Albert J Fornace; Hyuk-Jin Cha (1013-1022).
Mice null for wild-type p53-induced phosphatase 1 (WIP1) display defects in testis development and spermatogenesis, resulting in reduced fertility. However, the molecular mechanism underlying these abnormalities in the testis remains uncharacterized. We report that the phosphatase activity of WIP1 increases Wnt activity through Nemo-like kinase (NLK). WIP1 directly interacted with NLK, which is highly homologous to p38 MAPK, a WIP1 substrate, and dephosphorylated its activation site. The WIP1-mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer-binding factor 1 (LEF1), enhancing its interaction with β-catenin. Additionally, WIP1 depletion impaired germ cell development, as evidenced by the expression of Oct4 and the germ cell-specific markers Ddx4, Nanos3 and Dnd1 during the development of germ cells from Oct4-GFP transgenic (OG2) mouse embryonic stem cells (mESCs). The expression of WIP1, whose level was significantly lower after the differentiation of germ cells from mESCs, occurred in parallel with the expression of germ cell development markers and SRY-box 17 (Sox17), a downstream target of Wnt. These results indicate that WIP1 is essential for germ cell development, which is known to require Wnt activity.
Keywords: β-catenin; Dephosphorylation; Germ cell development; NLK; Wip1;