TY - JOUR AU - Tóth, Balázs István AU - Bahar, Bazeli AU - Annelies, Janssens AU - Lisztes, Erika AU - Racskó, Márk AU - Kelemen, Balázs AU - Herczeg, Mihály AU - Nagy, Tamás Milán AU - E Kövér, Katalin AU - Argha, Mitra AU - Attila, Borics AU - Bíró, Tamás AU - Thomas, Voets TI - Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants JF - ELIFE J2 - ELIFE PY - 2024 SN - 2050-084X UR - https://m2.mtmt.hu/api/publication/34722559 ID - 34722559 N1 - preprint DOI-ja: 10.1101/2024.02.01.578392 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Kinga Fanni AU - Ádám, Dorottya AU - Arany, József AU - Ramirez, Yesid A. AU - Bíró, Tamás AU - Drake, Jennifer I. AU - O'Mahony, Alison AU - Szöllősi, Attila AU - Póliska, Szilárd AU - Kilić, Ana AU - Soeberdt, Michael AU - Abels, Christoph AU - Oláh, Attila TI - Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release JF - EXPERIMENTAL DERMATOLOGY J2 - EXP DERMATOL VL - 33 PY - 2024 IS - 1 PG - 15 SN - 0906-6705 DO - 10.1111/exd.14988 UR - https://m2.mtmt.hu/api/publication/34484605 ID - 34484605 AB - Fluoxetine is a safe antidepressant with remarkable anti‐inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic‐polycytidylic acid (p(I:C))‐induced inflammatory model. We found that a non‐cytotoxic concentration (MTT‐assay, CyQUANT‐assay) of fluoxetine significantly suppressed p(I:C)‐induced expression and release of several pro‐inflammatory cytokines (Q‐PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF‐κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)‐induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3‐kinase (PI3K) pathway. Importantly, the PI3K‐inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q‐PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell‐free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA‐Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)‐treatment, and exerted an overall anti‐inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti‐inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses. LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Kinga Fanni AU - Ádám, Dorottya AU - Arany, József AU - Ramirez, Y.A. AU - Bíró, Tamás AU - Drake, J.I. AU - O’Mahony, A. AU - Szöllősi, Attila AU - Kilić, A. AU - Soeberdt, M. AU - Abels, C. AU - Oláh, H.A. TI - Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes, and suppresses their endothelin release JF - JOURNAL OF INVESTIGATIVE DERMATOLOGY J2 - J INVEST DERMATOL VL - 143 PY - 2023 IS - 11 SP - S361 SN - 0022-202X DO - 10.1016/j.jid.2023.09.181 UR - https://m2.mtmt.hu/api/publication/34493801 ID - 34493801 LA - English DB - MTMT ER - TY - JOUR AU - Tóth, Kinga Fanni AU - Ádám, Dorottya AU - Arany, József AU - Ramirez, Y.A. AU - Bíró, Tamás AU - Drake, J.I. AU - O’Mahony, A. AU - Szöllősi, Attila AU - Kilic, A. AU - Soeberdt, M. AU - Abels, C. AU - Oláh, Attila TI - Fluoxetine exerts anti-inflammatory effects on human epidermal keratinocytes, and suppresses endothelin release via inhibiting PI3K JF - JOURNAL OF INVESTIGATIVE DERMATOLOGY J2 - J INVEST DERMATOL VL - 143 PY - 2023 IS - 5 SP - S126 SN - 0022-202X DO - 10.1016/j.jid.2023.03.740 UR - https://m2.mtmt.hu/api/publication/34323650 ID - 34323650 LA - English DB - MTMT ER - TY - JOUR AU - Lendvai, Alexandra AU - Béke, Gabriella AU - Hollósi, Erika AU - Becker, Maike AU - Völker, Jörn Michael AU - Schulze zur Wiesche, Erik AU - Bácsi, Attila AU - Bíró, Tamás AU - Mihály, Johanna TI - N,N-Dimethylglycine Sodium Salt Exerts Marked Anti-Inflammatory Effects in Various Dermatitis Models and Activates Human Epidermal Keratinocytes by Increasing Proliferation, Migration, and Growth Factor Release JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 14 PG - 18 SN - 1661-6596 DO - 10.3390/ijms241411264 UR - https://m2.mtmt.hu/api/publication/34094289 ID - 34094289 AB - N,N-dimethylglycine (DMG) is a naturally occurring compound being widely used as an oral supplement to improve growth and physical performance. Thus far, its effects on human skin have not been described in the literature. For the first time, we show that N,N-dimethylglycine sodium salt (DMG-Na) promoted the proliferation of cultured human epidermal HaCaT keratinocytes. Even at high doses, DMG-Na did not compromise the cellular viability of these cells. In a scratch wound-closure assay, DMG-Na augmented the rate of wound closure, demonstrating that it promotes keratinocyte migration. Further, DMG-Na treatment of the cells resulted in the upregulation of the synthesis and release of specific growth factors. Intriguingly, DMG-Na also exerted robust anti-inflammatory and antioxidant effects, as assessed in three different models of human keratinocytes, mimicking microbial and allergic contact dermatitis as well as psoriasis and UVB irradiation-induced solar dermatitis. These results identify DMG-Na as a highly promising novel active compound to promote epidermal proliferation, regeneration, and repair, and to exert protective functions. Further preclinical and clinical studies are under investigation to prove the seminal impact of topically applied DMG-Na on relevant conditions of the skin and its appendages. LA - English DB - MTMT ER - TY - JOUR AU - Vincze, Anett AU - Lisztes, Erika AU - Szabó, Katalin AU - Béldi, Tibor Gábor AU - Nagy-Vincze, Melinda AU - Pór, Ágnes AU - Varga, József AU - Dankó, Katalin AU - Bíró, Tamás AU - Tóth, Balázs István AU - Griger, Zoltán TI - Pruritogenic molecules in the skin of patients with dermatomyositis JF - FRONTIERS IN MEDICINE J2 - FRONT MED VL - 10 PY - 2023 PG - 9 SN - 2296-858X DO - 10.3389/fmed.2023.1168359 UR - https://m2.mtmt.hu/api/publication/33854100 ID - 33854100 N1 - EDITED BY: Latika Gupta, Royal Wolverhampton Hospitals NHS Trust, United Kingdom REVIEWED BY - Klas Nordlind, Karolinska Institutet (KI), Sweden - Takashi Hashimoto, Osaka City University, Japan AB - Introduction: Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients. Methods: Interleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software. Results: A total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions. Discussion: Our results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration. LA - English DB - MTMT ER - TY - JOUR AU - Király, Sándor Balázs AU - Tóth, László AU - Kovács, Tibor AU - Bényei, Attila Csaba AU - Lisztes, Erika AU - Tóth, Balázs István AU - Bíró, Tamás AU - Kiss, Attila AU - E Kövér, Katalin AU - Mándi, Attila AU - Kurtán, Tibor TI - Multifaceted Domino Knoevenagel‐Cyclization Reactions; Four Movements for 2H‐Chromenes and Chromans JF - ADVANCED SYNTHESIS & CATALYSIS J2 - ADV SYNTH CATAL VL - 365 PY - 2023 IS - 19 SP - 3301 EP - 3319 PG - 19 SN - 1615-4150 DO - 10.1002/adsc.202300083 UR - https://m2.mtmt.hu/api/publication/33683947 ID - 33683947 AB - Domino Knoevenagel-cyclization reactions of 2H-chromene and chroman derivatives containing o-formylaryl amine or ether side-chain was carried out to produce four series of chiral condensed heterocycles representing four novel skeletons and exhibiting antiproliferative activity. The cyclization step occurred with four different mechanisms: a concerted intramolecular hetero Diels-Alder reaction (IMHDA), a stepwise polar [2+2] cycloaddition, a [1,5]-hydride shift-6-endo cyclization or a multi-step nitro hetero Diels-Alder-ring-opening-Cadogan-type cyclization sequence. The latter reaction provided a new route to hydroxyindoles by an inverse Cadogan-type cyclization, in which the nitro group is deoxygenated by a nitro IMHDA-ring-opening sequence. The cyclization mechanisms and their stereoselectivity were studied by DFT calculations, based on which we proposed a mechanism for the multi-step cyclization to hydroxyindoles and explained the observed diastereoselectivity. LA - English DB - MTMT ER - TY - JOUR AU - Sipka, Sándor AU - Bíró, Tamás AU - Czifra, Gabriella AU - Griger, Zoltán AU - Gergely, Pál AU - Brugós, Boglárka AU - Tarr, Tünde TI - The role of protein kinase C isoenzymes in the pathogenesis of human autoimmune diseases JF - CLINICAL IMMUNOLOGY J2 - CLIN IMMUNOL VL - 241 PY - 2022 PG - 5 SN - 1521-6616 DO - 10.1016/j.clim.2022.109071 UR - https://m2.mtmt.hu/api/publication/33027049 ID - 33027049 AB - The physiological role of protein kinase C (PKC) enzymes in the immune system is presented briefly. From earlier publications of others data were collected how the defects of one/two isoenzymes of PKC system suggested their involvement in the pathogenesis of human autoimmune diseases. Our observations on the defects of seven PKC isoenzymes in the peripheral blood mononuclear cells (PBMC) demonstrate that these molecular impairments are not prerequisits of the pathogenesis of systemic lupus erythematosus (SLE), mixed connective tissue disease and Sjögren's syndrome. However, these defects can modulate the disease activity and symptoms especially in SLE by several pathways. The role of PKC system in other forms of autoimmune diseases is also very small. It was of note that we detected decreased expression of PKC isoenzymes in PBMC of a European white family with an X-linked genetic background showing seasonal undulations in the lupus patient and also in her healthy mother. LA - English DB - MTMT ER - TY - JOUR AU - Vasas, Nikolett AU - Pénzes, Zsófia AU - Kistamás, Kornél AU - Nánási, Péter Pál AU - Molnár, Szabolcs AU - Szegedi, Andrea AU - Szöllősi, Attila AU - Bíró, Tamás TI - Transient Receptor Potential Vanilloid 3 Expression Is Increased In Non‐Lesional Skin Of Atopic Dermatitis Patients JF - EXPERIMENTAL DERMATOLOGY J2 - EXP DERMATOL VL - 31 PY - 2022 IS - 5 SP - 807 EP - 813 PG - 7 SN - 0906-6705 DO - 10.1111/exd.14530 UR - https://m2.mtmt.hu/api/publication/32612618 ID - 32612618 AB - TRPV3 (transient receptor potential vanilloid 3) is a pro-inflammatory ion channel mostly expressed by keratinocytes of the human skin. Previous studies have shown that the expression of TRPV3 is markedly upregulated in the lesional epidermis of atopic dermatitis (AD) patients suggesting a potential pathogenetic role of the ion channel in the disease. In the current study, we aimed at defining the molecular and functional expression of TRPV3 in non-lesional skin of AD patients as previous studies implicated that healthy-appearing skin in AD are markedly distinct from normal skin with respect to terminal differentiation and certain immune function abnormalities. By using multiple, complementary immunolabeling and RT-qPCR technologies on full-thickness and epidermal shave biopsy samples from AD patients (lesional, non-lesional) and healthy volunteers, we provide the first evidence that the expression of TRPV3 is markedly upregulated in non-lesional human AD epidermis, similar to lesional AD samples. Of further importance, by using the patch-clamp method on cultured healthy and non-lesional AD keratinocytes, we also show that this upregulation is functional as determined by the significantly augmented TRPV3-specific ion current (induced by agonists) on cultured non-lesional AD keratinocytes when compared to healthy ones. LA - English DB - MTMT ER - TY - JOUR AU - Király, Sándor Balázs AU - Bényei, Attila Csaba AU - Lisztes, Erika AU - Bíró, Tamás AU - Tóth, Balázs István AU - Kurtán, Tibor TI - Knoevenagel-Cyclization Cascade Reactions of Substituted 5,6-Dihydro-2H-Pyran Derivatives JF - EUROPEAN JOURNAL OF ORGANIC CHEMISTRY J2 - EUR J ORG CHEM VL - 2021 PY - 2021 IS - 45 SP - 6161 EP - 6170 PG - 10 SN - 1434-193X DO - 10.1002/ejoc.202101277 UR - https://m2.mtmt.hu/api/publication/32596154 ID - 32596154 AB - The diastereoselective domino-Knoevenagel-IMHDA reactions of 5,6-dihydro-2H-pyran derivatives containing an o-formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel-[1,5]-hydride shiftcyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6-dihydro-2H-pyran-3-yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X-ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC50 values down to 2.99 μM. LA - English DB - MTMT ER -