TY - JOUR AU - Hudak, Anett AU - Jósvay, Katalin AU - Racskóné Domonkos, Ildikó AU - Letoha, Annamária AU - Szilák, László AU - Letoha, Tamás TI - The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 13 PG - 17 SN - 1661-6596 DO - 10.3390/ijms22137070 UR - https://m2.mtmt.hu/api/publication/32106321 ID - 32106321 N1 - Funding Agency and Grant Number: Innovative Medicines Initiative 2 Joint Undertaking [807015]; European Union's Horizon 2020 research and innovation programme; EFPIA; European Union's Horizon 2020 Research and Innovation Programme under Future and Emerging Technologies [863214]; National Research, Development and Innovation Office, HungaryNational Research, Development & Innovation Office (NRDIO) - Hungary [GINOP-2.1.2-8-1-4-16-2017-00234, EUREKA_16-1-20170018, 2019-2.1.1-EUREKA-2019-00007, 2017-2.3.6-TET-CN-2018-00023] Funding text: A.H., L.S. and T.L. have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 807015. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. A.H., L.S. and T.L. have also received funding from the European Union's Horizon 2020 Research and Innovation Programme under Future and Emerging Technologies grant agreement No. 863214. A.H., L.S. and T.L. have also been supported by GINOP-2.1.2-8-1-4-16-2017-00234 and grants EUREKA_16-1-20170018, 2019-2.1.1-EUREKA-2019-00007 and 2017-2.3.6-TET-CN-2018-00023 of the National Research, Development and Innovation Office, Hungary. AB - Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer's disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (A beta). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in A beta pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE-heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated A beta uptake and aggregation. ApoE2 increased the cellular internalization of monomeric A beta, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once A beta aggregated: while ApoE2 reduced the uptake of A beta aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4 ' s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of A beta pathology. LA - English DB - MTMT ER - TY - JOUR AU - Barna, Lilla AU - Walter, Fruzsina AU - Harazin, András AU - Bocsik, Alexandra AU - Kincses, András AU - Tubak, Vilmos AU - Jósvay, Katalin AU - Zvara, Ágnes AU - Campos-Bedolla, Patricia AU - Deli, Mária Anna TI - Simvastatin, edaravone and dexamethasone protect against kainate-induced brain endothelial cell damage. JF - FLUIDS AND BARRIERS OF THE CNS J2 - FLUIDS BARRIERS CNS VL - 17 PY - 2020 IS - 1 PG - 13 SN - 2045-8118 DO - 10.1186/s12987-019-0166-1 UR - https://m2.mtmt.hu/api/publication/31181444 ID - 31181444 N1 - Lilla Barna, Fruzsina R. Walter and András Harazin contributed equally to the manuscript. AB - Excitotoxicity is a central pathological pathway in many neurological diseases with blood-brain barrier (BBB) dysfunction. Kainate, an exogenous excitotoxin, induces epilepsy and BBB damage in animal models, but the direct effect of kainate on brain endothelial cells has not been studied in detail. Our aim was to examine the direct effects of kainate on cultured cells of the BBB and to test three anti-inflammatory and antioxidant drugs used in clinical practice, simvastatin, edaravone and dexamethasone, to protect against kainate-induced changes.Primary rat brain endothelial cell, pericyte and astroglia cultures were used to study cell viability by impedance measurement. BBB permeability was measured on a model made from the co-culture of the three cell types. The production of nitrogen monoxide and reactive oxygen species was followed by fluorescent probes. The mRNA expression of kainate receptors and nitric oxide synthases were studied by PCR.Kainate damaged brain endothelial cells and made the immunostaining of junctional proteins claudin-5 and zonula occludens-1 discontinuous at the cell border indicating the opening of the barrier. The permeability of the BBB model for marker molecules fluorescein and albumin and the production of nitric oxide in brain endothelial cells were increased by kainate. Simvastatin, edaravone and dexamethasone protected against the reduced cell viability, increased permeability and the morphological changes in cellular junctions caused by kainate. Dexamethasone attenuated the elevated nitric oxide production and decreased the inducible nitric oxide synthase (NOS2/iNOS) mRNA expression increased by kainate treatment.Kainate directly damaged cultured brain endothelial cells. Simvastatin, edaravone and dexamethasone protected the BBB model against kainate-induced changes. Our results confirmed the potential clinical usefulness of these drugs to attenuate BBB damage. LA - English DB - MTMT ER - TY - JOUR AU - Hudak, Anett AU - Kusz, Erzsebet AU - Racskóné Domonkos, Ildikó AU - Jósvay, Katalin AU - Kodamullil, Alpha Tom AU - Szilák, László AU - Hofmann-Apitius, Martin AU - Letoha, Tamás TI - Contribution of syndecans to cellular uptake and fibrillation of alpha-synuclein and tau JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 IS - 1 SN - 2045-2322 DO - 10.1038/s41598-019-53038-z UR - https://m2.mtmt.hu/api/publication/30935380 ID - 30935380 N1 - Pharmacoidea Ltd., Szeged, H-6726, Hungary Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, 53754, Germany Szilak Laboratories, Bioinformatics and Molecule-Design, Szeged, H-6723, Hungary Export Date: 18 February 2020 Correspondence Address: Letoha, T.; Pharmacoidea Ltd.Hungary; email: tamas.letoha@pharmacoidea.eu AB - Scientific evidence suggests that alpha-synuclein and tau have prion-like properties and that prionlike spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Heparan sulfate proteoglycans (HSPGs) in the plasma membrane support this process by attaching misfolded protein fibrils. Despite of intense studies, contribution of specific HSPGs to seeding and spreading of alpha-synuclein and tau has not been explored yet. Here we report that members of the syndecan family of HSPGs mediate cellular uptake of alpha-synuclein and tau fibrils via a lipid-raft dependent and clathrin-independent endocytic route. Among syndecans, the neuron predominant syndecan-3 exhibits the highest affinity for both alpha-synuclein and tau. Syndecan-mediated internalization of alpha-synuclein and tau depends heavily on conformation as uptake via syndecans start to dominate once fibrils are formed. Overexpression of syndecans, on the other hand, reduces cellular uptake of monomeric alpha-synuclein and tau, yet exerts a fibril forming effect on both proteins. Data obtained from syndecan overexpressing cellular models presents syndecans, especially the neuron predominant syndecan-3, as important mediators of seeding and spreading of alpha-synuclein and tau and reveal how syndecans contribute to fundamental molecular events of a-synuclein and tau pathology. LA - English DB - MTMT ER - TY - JOUR AU - Letoha, Tamás AU - Hudák, Anett AU - Kusz, Erzsébet AU - Pettkó-Szandtner, Aladár AU - Racskóné Domonkos, Ildikó AU - Jósvay, Katalin AU - Hofmann-Apitius, Martin AU - Szilák, László TI - Contribution of syndecans to cellular internalization and fibrillation of amyloid-β (1–42) JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 IS - 1 PG - 17 SN - 2045-2322 DO - 10.1038/s41598-018-37476-9 UR - https://m2.mtmt.hu/api/publication/30462206 ID - 30462206 N1 - Pharmacoidea Ltd., Szeged, H-6726, Hungary Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, 53754, Germany Szilak Laboratories, Bioinformatics and Molecule-Design, Szeged, H-6723, Hungary Cited By :3 Export Date: 18 February 2020 Correspondence Address: Letoha, T.; Pharmacoidea Ltd.Hungary; email: tamas.letoha@pharmacoidea.eu Pharmacoidea Ltd., Szeged, H-6726, Hungary Biological Research Centre of the Hungarian Academy of Sciences, Szeged, H-6726, Hungary Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Sankt Augustin, 53754, Germany Szilak Laboratories, Bioinformatics and Molecule-Design, Szeged, H-6723, Hungary Cited By :3 Export Date: 20 February 2020 Correspondence Address: Letoha, T.; Pharmacoidea Ltd.Hungary; email: tamas.letoha@pharmacoidea.eu AB - Intraneuronal accumulation of amyloid-beta(1-42) (A beta 1-42) is one of the earliest signs of Alzheimer's disease (AD). Cell surface heparan sulfate proteoglycans (HSPGs) have profound influence on the cellular uptake of A beta 1-42 by mediating its attachment and subsequent internalization into the cells. Colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have already been reported in postmortem AD brains. Considering the growing evidence on the involvement of syndecans in the pathogenesis of AD, we analyzed the contribution of syndecans to cellular uptake and fibrillation of A beta 1-42. Among syndecans, the neuron specific syndecan-3 isoform increased cellular uptake of A beta 1-42 the most. Kinetics of A beta 1-42 uptake also proved to be fairly different among SDC family members: syndecan-3 increased A beta 1-42 uptake from the earliest time points, while other syndecans facilitated A beta 1-42 internalization at a slower pace. Internalized A beta 1-42 colocalized with syndecans and flotillins, highlighting the role of lipid-rafts in syndecan-mediated uptake. Syndecan-3 and 4 also triggered fibrillation of A beta 1-42, further emphasizing the pathophysiological relevance of syndecans in plaque formation. Overall our data highlight syndecans, especially the neuron-specific syndecan-3 isoform, as important players in amyloid pathology and show that syndecans, regardless of cell type, facilitate key molecular events in neurodegeneration. LA - English DB - MTMT ER - TY - JOUR AU - Nazıroğlu, M AU - Blum, W AU - Jósvay, Katalin AU - Çiğ, B AU - Henzi, T AU - Oláh, Zoltán AU - Vizler, Csaba AU - Schwaller, B AU - Pecze, László TI - Menthol evokes Ca2+ signals and induces oxidative stress independently of the presence of TRPM8 (menthol) receptor in cancer cells JF - REDOX BIOLOGY J2 - REDOX BIOL VL - 14 PY - 2018 SP - 439 EP - 449 PG - 11 SN - 2213-2317 DO - 10.1016/j.redox.2017.10.009 UR - https://m2.mtmt.hu/api/publication/3318960 ID - 3318960 N1 - Cited By :18 Export Date: 16 September 2022 AB - Menthol is a naturally occurring monoterpene alcohol possessing remarkable biological properties including antipruritic, analgesic, antiseptic, anti-inflammatory and cooling effects. Here, we examined the menthol-evoked Ca2+ signals in breast and prostate cancer cell lines. The effect of menthol (50–500 µM) was predicted to be mediated by the transient receptor potential ion channel melastatin subtype 8 (TRPM8). However, the intensity of menthol-evoked Ca2+ signals did not correlate with the expression levels of TRPM8 in breast and prostate cancer cells indicating a TRPM8-independent signaling pathway. Menthol-evoked Ca2+ signals were analyzed in detail in Du 145 prostate cancer cells, as well as in CRISPR/Cas9 TRPM8-knockout Du 145 cells. Menthol (500 µM) induced Ca2+ oscillations in both cell lines, thus independent of TRPM8, which were however dependent on the production of inositol trisphosphate. Results based on pharmacological tools point to an involvement of the purinergic pathway in menthol-evoked Ca2+ responses. Finally, menthol (50–500 µM) decreased cell viability and induced oxidative stress independently of the presence of TRPM8 channels, despite that temperature-evoked TRPM8-mediated inward currents were significantly decreased in TRPM8-knockout Du 145 cells compared to wild type Du 145 cells. © 2017 The Authors LA - English DB - MTMT ER - TY - JOUR AU - Oláh, Zoltán AU - Rédei, Dóra AU - Pecze, László AU - Vizler, Csaba AU - Jósvay, Katalin AU - Forgó, Péter AU - Winter, Zoltán AU - Dombi, György AU - Szakonyi, Gerda AU - Hohmann, Judit TI - Pellitorine, an extract of Tetradium daniellii, is an antagonist of the ion channel TRPV1 JF - PHYTOMEDICINE: INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY J2 - PHYTOMEDICINE VL - 34 PY - 2017 SP - 44 EP - 49 PG - 6 SN - 0944-7113 DO - 10.1016/j.phymed.2017.06.006 UR - https://m2.mtmt.hu/api/publication/3260664 ID - 3260664 LA - English DB - MTMT ER - TY - JOUR AU - Naziroglu, M AU - Cig, B AU - Blum, W AU - Vizler, Csaba AU - Buhala, Andrea AU - Marton, Annamária AU - Katona, Róbert László AU - Jósvay, Katalin AU - Schwaller, B AU - Oláh, Zoltán AU - Pecze, László TI - Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels JF - PLOS ONE J2 - PLOS ONE VL - 12 PY - 2017 IS - 6 PG - 19 SN - 1932-6203 DO - 10.1371/journal.pone.0179950 UR - https://m2.mtmt.hu/api/publication/3250677 ID - 3250677 N1 - OA gold AB - There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 mu M) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 mu M) either alone or together with CAPS (10 mu M). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicinevoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 mu M). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required. LA - English DB - MTMT ER - TY - JOUR AU - Pecze, L AU - Jósvay, Katalin AU - Blum, W AU - Petrovics, G AU - Vizler, Csaba AU - Oláh, Zoltán AU - Schwaller, B TI - Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH J2 - BBA-MOL CELL RES VL - 1863 PY - 2016 IS - 8 SP - 2054 EP - 2064 PG - 11 SN - 0167-4889 DO - 10.1016/j.bbamcr.2016.05.007 UR - https://m2.mtmt.hu/api/publication/3095574 ID - 3095574 N1 - Megjegyzés-27115000 N1 Funding details: 130680, SNF, Stavros Niarchos Foundation AB - Vanilloids including capsaicin and resiniferatoxin are potent transient receptor potential vanilloid type I (TRPV1) agonists. TRPV1 overstimulation selectively ablates capsaicin-sensitive sensory neurons in animal models in vivo. The cytotoxic mechanisms are based on strong Na+ and Ca2+ influx via TRPV1 channels, which leads to mitochondrial Ca2+ accumulation and necrotic cell swelling. Increased TRPV1 expression levels are also observed in breast and prostate cancer and derived cell lines. Here, we examined whether potent agonist-induced over stimulation mediated by TRPV1 might represent a means for the eradication of prostate carcinoma (PC-3, Du 145, LNCaP) and breast cancer (MCF7, MDA-MB-231, BT-474) cells in vitro. While rat sensory neurons were highly vanilloid-sensitive, normal rat prostate epithelial cells were resistant in vivo. We found TRPV1 to be expressed in all cancer cell lines at mRNA and protein levels, yet protein expression levels were significantly lower compared to sensory neurons. Treatment of all human carcinoma cell lines with capsaicin didn't lead to overstimulation cytotoxicity in vitro. We assume that the low vanilloid-sensitivity of prostate and breast cancer cells is associated with low expression levels of TRPV1, since ectopic TRPV1 expression rendered them susceptible to the cytotoxic effect of vanilloids evidenced by plateau-type Ca2+ signals, mitochondrial Ca2+ accumulation and Na+- and Ca2+-dependent membrane disorganization. Moreover, long-term monitoring revealed that merely the ectopic expression of TRPV1 stopped cell proliferation and often induced apoptotic processes via strong activation of caspase-3 activity. Our results indicate that specific targeting of TRPV1 function remains a putative strategy for cancer treatment. (C) 2016 The Authors. Published by Elsevier B.V. LA - English DB - MTMT ER - TY - JOUR AU - Hetényi, Anasztázia AU - Németh, Lukács AU - Wéber, Edit AU - Szakonyi, Gerda AU - Winter, Zoltán AU - Jósvay, Katalin AU - Bartus, Éva AU - Oláh, Zoltán AU - Martinek, Tamás TI - Competitive inhibition of TRPV1 – calmodulin interaction by vanilloids JF - FEBS LETTERS J2 - FEBS LETT VL - 590 PY - 2016 IS - 16 SP - 2768 EP - 2775 PG - 8 SN - 0014-5793 DO - 10.1002/1873-3468.12267 UR - https://m2.mtmt.hu/api/publication/3087152 ID - 3087152 N1 - Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001]\n Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'.\n Funding Agency and Grant Number: Hungarian Academy of Sciences; Lendulet Program [LP-2011-009]; MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. [TP7-017]; Hungarian Research Foundation [OTKA K112442]; Richter Gedeon Talentum Alapitvany; European Union; State of Hungary; European Social Fund [TAMOP-4.2.4.A/ 2-11/1-2012-0001] Funding text: This work was supported by the Hungarian Academy of Sciences, Lendulet Program (LP-2011-009), MTA Postdoctoral Fellowship E.W., Gedeon Richter Plc. (TP7-017), the Hungarian Research Foundation (OTKA K112442) and Financial support from Richter Gedeon Talentum Alapitvany (Ph.D. Scholarship to E.B.). This research was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TAMOP-4.2.4.A/ 2-11/1-2012-0001 'National Excellence Program'. AB - There is enormous interest toward vanilloid agonists of the pain receptor TRPV1 in analgesic therapy, but the mechanisms of their sensory neuron-blocking effects at high or repeated doses are still a matter of debate. Our results have demonstrated that capsaicin and resiniferatoxin form nanomolar complexes with calmodulin, and competitively inhibit TRPV1-calmodulin interaction. These interactions involve the protein recognition interface of calmodulin, which is responsible for all of the cell-regulatory calmodulin-protein interactions. These results draw attention to a previously unknown vanilloid target, which may contribute to the explanation of the paradoxical pain-modulating behavior of these important pharmacons. LA - English DB - MTMT ER - TY - JOUR AU - Glatz, Attila AU - Pilbat, Ana Maria AU - Nemeth, GL AU - Kontár, Katalin AU - Jósvay, Katalin AU - Hunya, Ákos AU - Udvardy, Andor AU - Gombos, Imre AU - Péter, Mária AU - Balogh, Gábor AU - Horváth, Ibolya AU - Vigh, László AU - Török, Zsolt TI - Involvement of small heat shock proteins, trehalose, and lipids in the thermal stress management in Schizosaccharomyces pombe. JF - CELL STRESS & CHAPERONES J2 - CELL STRESS CHAPERON VL - 21 PY - 2016 IS - 2 SP - 327 EP - 338 PG - 12 SN - 1355-8145 DO - 10.1007/s12192-015-0662-4 UR - https://m2.mtmt.hu/api/publication/2990307 ID - 2990307 N1 - Export Date: 20 June 2019 CODEN: CSCHF Cited By :24 Export Date: 27 May 2021 CODEN: CSCHF Correspondence Address: Török, Z.; Institute of Biochemistry, Hungary; email: torok.zsolt@brc.mta.hu AB - Changes in the levels of three structurally and functionally different important thermoprotectant molecules, namely small heat shock proteins (sHsps), trehalose, and lipids, have been investigated upon heat shock in Schizosaccharomyces pombe. Both alpha-crystallin-type sHsps (Hsp15.8 and Hsp16) were induced after prolonged high-temperature treatment but with different kinetic profiles. The shsp null mutants display a weak, but significant, heat sensitivity indicating their importance in the thermal stress management. The heat induction of sHsps is different in wild type and in highly heat-sensitive trehalose-deficient (tps1Delta) cells; however, trehalose level did not show significant alteration in shsp mutants. The altered timing of trehalose accumulation and induction of sHsps suggest that the disaccharide might provide protection at the early stage of the heat stress while elevated amount of sHsps are required at the later phase. The cellular lipid compositions of two different temperature-adapted wild-type S. pombe cells are also altered according to the rule of homeoviscous adaptation, indicating their crucial role in adapting to the environmental temperature changes. Both Hsp15.8 and Hsp16 are able to bind to different lipids isolated from S. pombe, whose interaction might provide a powerful protection against heat-induced damages of the membranes. Our data suggest that all the three investigated thermoprotectant macromolecules play a pivotal role during the thermal stress management in the fission yeast. LA - English DB - MTMT ER -