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Dr. Florian Lang
Physiologisches Institut I, Universität Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany

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0 mechanisms and clinical significance of cell volume regulation
0 erythrocyte death signaling
0 serum-and glucocorticoid inducible kinase isoforms
0 physiology and pharmacology of human ion channels and carriers expressed in oocytes
0 host cell physiology in hostpathogen interaction

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serum-and glucocorticoid inducible kinase isoforms
mechanisms of apoptotic cell death

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Journal article
Published: 28 July 2021 in Biology
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Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. Accumulating evidence demonstrates that alpha-synuclein (α-Syn), an apparently predominant neuronal protein, is a major contributor to PD pathology. As α-Syn is also highly abundant in blood, particularly in red blood cells (RBCs) and platelets, this in turn raises the question on the function of presumably dysfunctional α-Syn in “peripheral” cells and its putative effect on the other enclosed constituents. Herein, we detected the internal variance in erythrocytes of PD patients by Raman spectroscopy, but no measurable amount of erythrocytic behavioural change (eryptosis) or any haemoglobin variation was noticed. An elevated level of plasmin-antiplasmin complexes (PAP) was observed in the plasma of PD patients, indicating activation of the fibrinolytic system, but platelet activation after thrombin stimulation was not altered. Sex-specific patterns were noticed for blood coagulation factor XIII and factor XII activity in PD patients. Additionally, the alterations in homocysteine levels which have often been observed in PD patients were found to be independent from L-DOPA usage and PAP levels. Furthermore, a selective gene expression analysis identified subsets of genes related to different blood-associated compartments (RBCs, platelets, coagulation-fibrinolysis) also involved in PD-related pathways.

ACS Style

Amit Sharma; Jens Müller; Karin Schuetze; Verena Rolfes; Rosi Bissinger; Nathalia Rosero; Ashar Ahmad; Bernardo S Franklin; Berndt Zur; Holger Fröhlich; Florian Lang; Johannes Oldenburg; Bernd Pötzsch; Ullrich Wüllner. Comprehensive Profiling of Blood Coagulation and Fibrinolysis Marker Reveals Elevated Plasmin-Antiplasmin Complexes in Parkinson’s Disease. Biology 2021, 10, 716 .

AMA Style

Amit Sharma, Jens Müller, Karin Schuetze, Verena Rolfes, Rosi Bissinger, Nathalia Rosero, Ashar Ahmad, Bernardo S Franklin, Berndt Zur, Holger Fröhlich, Florian Lang, Johannes Oldenburg, Bernd Pötzsch, Ullrich Wüllner. Comprehensive Profiling of Blood Coagulation and Fibrinolysis Marker Reveals Elevated Plasmin-Antiplasmin Complexes in Parkinson’s Disease. Biology. 2021; 10 (8):716.

Chicago/Turabian Style

Amit Sharma; Jens Müller; Karin Schuetze; Verena Rolfes; Rosi Bissinger; Nathalia Rosero; Ashar Ahmad; Bernardo S Franklin; Berndt Zur; Holger Fröhlich; Florian Lang; Johannes Oldenburg; Bernd Pötzsch; Ullrich Wüllner. 2021. "Comprehensive Profiling of Blood Coagulation and Fibrinolysis Marker Reveals Elevated Plasmin-Antiplasmin Complexes in Parkinson’s Disease." Biology 10, no. 8: 716.

Journal article
Published: 10 May 2021 in Journal of Personalized Medicine
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Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

ACS Style

Kevin Peikert; Hannes Glaß; Enrica Federti; Alessandro Matte; Lisann Pelzl; Katja Akgün; Tjalf Ziemssen; Rainer Ordemann; Florian Lang; The Network for Translational Research for Neuroacanthocytosis Patients; Lucia De Franceschi; Andreas Hermann. Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease. Journal of Personalized Medicine 2021, 11, 392 .

AMA Style

Kevin Peikert, Hannes Glaß, Enrica Federti, Alessandro Matte, Lisann Pelzl, Katja Akgün, Tjalf Ziemssen, Rainer Ordemann, Florian Lang, The Network for Translational Research for Neuroacanthocytosis Patients, Lucia De Franceschi, Andreas Hermann. Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease. Journal of Personalized Medicine. 2021; 11 (5):392.

Chicago/Turabian Style

Kevin Peikert; Hannes Glaß; Enrica Federti; Alessandro Matte; Lisann Pelzl; Katja Akgün; Tjalf Ziemssen; Rainer Ordemann; Florian Lang; The Network for Translational Research for Neuroacanthocytosis Patients; Lucia De Franceschi; Andreas Hermann. 2021. "Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease." Journal of Personalized Medicine 11, no. 5: 392.

Journal article
Published: 24 March 2021 in International Journal of Molecular Sciences
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In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.

ACS Style

Kuo Zhou; Xuexue Zhu; Ke Ma; Jibin Liu; Bernd Nürnberg; Meinrad Gawaz; Florian Lang. Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes. International Journal of Molecular Sciences 2021, 22, 3292 .

AMA Style

Kuo Zhou, Xuexue Zhu, Ke Ma, Jibin Liu, Bernd Nürnberg, Meinrad Gawaz, Florian Lang. Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes. International Journal of Molecular Sciences. 2021; 22 (7):3292.

Chicago/Turabian Style

Kuo Zhou; Xuexue Zhu; Ke Ma; Jibin Liu; Bernd Nürnberg; Meinrad Gawaz; Florian Lang. 2021. "Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes." International Journal of Molecular Sciences 22, no. 7: 3292.

Original article
Published: 07 January 2021 in Journal of Molecular Medicine
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Vascular calcification may result from stimulation of osteogenic signalling with upregulation of the transcription factors CBFA1, MSX2 and SOX9, as well as alkaline phosphatase (ALPL), which degrades and thus inactivates the calcification inhibitor pyrophosphate. Osteogenic signalling further involves upregulation of the Ca2+-channel ORAI1. The channel is activated by STIM1 and then accomplishes store-operated Ca2+ entry. ORAI1 and STIM1 are upregulated by the serum & glucocorticoid inducible kinase 1 (SGK1) which is critically important for osteogenic signalling. Stimulators of vascular calcification include vasopressin. The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to vasopressin upregulates ORAI1 and/or STIM1 expression, store-operated Ca2+ entry and osteogenic signalling. To this end, HAoSMCs were exposed to vasopressin (100 nM, 24 h) without or with additional exposure to ORAI1 blocker MRS1845 (10 μM) or SGK1 inhibitor GSK-650394 (1 μM). Transcript levels were measured using q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and store-operated Ca2+ entry from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 μM). As a result, vasopressin enhanced the transcript levels of ORAI1 and STIM1, store-operated Ca2+ entry, as well as the transcript levels of CBFA1, MSX2, SOX9 and ALPL. The effect of vasopressin on store-operated Ca2+ entry as well as on transcript levels of CBFA1, MSX2, SOX9 and ALPL was virtually abrogated by MRS1845 and GSK-650394. In conclusion, vasopressin stimulates expression of ORAI1/STIM1, thus augmenting store-operated Ca2+ entry and osteogenic signalling. In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394. • In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. • VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). • VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. • VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394.

ACS Style

Xuexue Zhu; Ke Ma; Kuo Zhou; Jibin Liu; Bernd Nürnberg; Florian Lang. Vasopressin-stimulated ORAI1 expression and store-operated Ca2+ entry in aortic smooth muscle cells. Journal of Molecular Medicine 2021, 99, 373 -382.

AMA Style

Xuexue Zhu, Ke Ma, Kuo Zhou, Jibin Liu, Bernd Nürnberg, Florian Lang. Vasopressin-stimulated ORAI1 expression and store-operated Ca2+ entry in aortic smooth muscle cells. Journal of Molecular Medicine. 2021; 99 (3):373-382.

Chicago/Turabian Style

Xuexue Zhu; Ke Ma; Kuo Zhou; Jibin Liu; Bernd Nürnberg; Florian Lang. 2021. "Vasopressin-stimulated ORAI1 expression and store-operated Ca2+ entry in aortic smooth muscle cells." Journal of Molecular Medicine 99, no. 3: 373-382.

Journal article
Published: 31 December 2020 in Neurosignals
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The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson’s disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson’s disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson’s disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca2+ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)2D3 production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)2D3 formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)2D3 formation, an effect requiring Klotho. 1,25(OH)2D3 is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)2D3 and excessive 1,25(OH)2D3 formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)2D3 is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)2D3 is considered to favorably influence the clinical course of Parkinson’s disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson’s disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)2D3 in the pathophysiology of Parkinson’s disease and its sensitivity to milk consumption.

ACS Style

Florian Lang; Ke Ma; Christina B. Leibrock; Madhuri S. Salker; Yogesh Singh. The Putative Role of 1,25(OH)2D3 in the Association of Milk Consumption and Parkinson’s Disease. Neurosignals 2020, 28, 14 -24.

AMA Style

Florian Lang, Ke Ma, Christina B. Leibrock, Madhuri S. Salker, Yogesh Singh. The Putative Role of 1,25(OH)2D3 in the Association of Milk Consumption and Parkinson’s Disease. Neurosignals. 2020; 28 (1):14-24.

Chicago/Turabian Style

Florian Lang; Ke Ma; Christina B. Leibrock; Madhuri S. Salker; Yogesh Singh. 2020. "The Putative Role of 1,25(OH)2D3 in the Association of Milk Consumption and Parkinson’s Disease." Neurosignals 28, no. 1: 14-24.

Review article
Published: 21 October 2020 in Frontiers in Cell and Developmental Biology
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The serum- and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na+/K+-ATPase as well as ion-, glucose-, and amino acid- carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na+-, Ca2+-, K+- and Cl– channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.

ACS Style

Florian Lang; Janet Rajaxavier; Yogesh Singh; Sara Y. Brucker; Madhuri S. Salker. The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium. Frontiers in Cell and Developmental Biology 2020, 8, 556543 .

AMA Style

Florian Lang, Janet Rajaxavier, Yogesh Singh, Sara Y. Brucker, Madhuri S. Salker. The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium. Frontiers in Cell and Developmental Biology. 2020; 8 ():556543.

Chicago/Turabian Style

Florian Lang; Janet Rajaxavier; Yogesh Singh; Sara Y. Brucker; Madhuri S. Salker. 2020. "The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium." Frontiers in Cell and Developmental Biology 8, no. : 556543.

Journal article
Published: 30 September 2020 in Scientific Reports
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The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1−/− mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1−/− mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

ACS Style

Yogesh Singh; Christoph Trautwein; Achal Dhariwal; Madhuri S. Salker; Alauddin; Laimdota Zizmare; Lisann Pelzl; Martina Feger; Jakob Admard; Nicolas Casadei; Michael Föller; Vivek Pachauri; David S. Park; Tak W. Mak; Julia-Stefanie Frick; Diethelm Wallwiener; Sara Y. Brucker; Florian Lang; Olaf Riess. DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs). Scientific Reports 2020, 10, 1 -19.

AMA Style

Yogesh Singh, Christoph Trautwein, Achal Dhariwal, Madhuri S. Salker, Alauddin, Laimdota Zizmare, Lisann Pelzl, Martina Feger, Jakob Admard, Nicolas Casadei, Michael Föller, Vivek Pachauri, David S. Park, Tak W. Mak, Julia-Stefanie Frick, Diethelm Wallwiener, Sara Y. Brucker, Florian Lang, Olaf Riess. DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs). Scientific Reports. 2020; 10 (1):1-19.

Chicago/Turabian Style

Yogesh Singh; Christoph Trautwein; Achal Dhariwal; Madhuri S. Salker; Alauddin; Laimdota Zizmare; Lisann Pelzl; Martina Feger; Jakob Admard; Nicolas Casadei; Michael Föller; Vivek Pachauri; David S. Park; Tak W. Mak; Julia-Stefanie Frick; Diethelm Wallwiener; Sara Y. Brucker; Florian Lang; Olaf Riess. 2020. "DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)." Scientific Reports 10, no. 1: 1-19.

Journal article
Published: 29 September 2020 in International Journal of Molecular Sciences
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In diabetes mellitus, hyperglycemia promotes the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) to enhance medial vascular calcification, a common complication strongly associated with cardiovascular disease and mortality. The mechanisms involved are, however, still poorly understood. Therefore, the present study explored the potential role of serum- and glucocorticoid-inducible kinase 1 (SGK1) during vascular calcification promoted by hyperglycemic conditions. Exposure to high-glucose conditions up-regulated the SGK1 expression in primary human aortic VSMCs. High glucose increased osteogenic marker expression and activity and, thus, promoted the osteogenic transdifferentiation of VSMCs, effects significantly suppressed by additional treatment with the SGK1 inhibitor EMD638683. Moreover, high glucose augmented the mineralization of VSMCs in the presence of calcification medium, effects again significantly reduced by SGK1 inhibition. Similarly, SGK1 knockdown blunted the high glucose-induced osteogenic transdifferentiation of VSMCs. The osteoinductive signaling promoted by high glucose required SGK1-dependent NF-kB activation. In addition, advanced glycation end products (AGEs) increased the SGK1 expression in VSMCs, and SGK1 inhibition was able to interfere with AGEs-induced osteogenic signaling. In conclusion, SGK1 is up-regulated and mediates, at least partly, the osteogenic transdifferentiation and calcification of VSMCs during hyperglycemic conditions. Thus, SGK1 inhibition may reduce the development of vascular calcification promoted by hyperglycemia in diabetes.

ACS Style

Florian Poetsch; Laura A. Henze; Misael Estepa; Barbara Moser; Burkert Pieske; Florian Lang; Kai-Uwe Eckardt; Ioana Alesutan; Jakob Voelkl. Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions. International Journal of Molecular Sciences 2020, 21, 7207 .

AMA Style

Florian Poetsch, Laura A. Henze, Misael Estepa, Barbara Moser, Burkert Pieske, Florian Lang, Kai-Uwe Eckardt, Ioana Alesutan, Jakob Voelkl. Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions. International Journal of Molecular Sciences. 2020; 21 (19):7207.

Chicago/Turabian Style

Florian Poetsch; Laura A. Henze; Misael Estepa; Barbara Moser; Burkert Pieske; Florian Lang; Kai-Uwe Eckardt; Ioana Alesutan; Jakob Voelkl. 2020. "Role of SGK1 in the Osteogenic Transdifferentiation and Calcification of Vascular Smooth Muscle Cells Promoted by Hyperglycemic Conditions." International Journal of Molecular Sciences 21, no. 19: 7207.

Original research article
Published: 14 August 2020 in Frontiers in Cell and Developmental Biology
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A limited window of receptivity is a prerequisite of reproductive success. Indispensable receptivity genes include cyclooxygenase 2 (COX2), an enzyme accomplishing formation of prostaglandin E2 (PGE2). A powerful regulator of PGE2 formation is Annexin A7 (ANXA7). The present study thus explored whether ANXA7 impacts on implantation and fertility. Here we show that ANXA7 is expressed in endometrial tissue and increases upon decidual transformation of human endometrial stromal cells (HESCs) in a time-dependent manner. Silencing ANXA7 significantly decreased the expression of PRL and IGFBP1, canonical decidual marker genes, but enhances COX2 and PGE2 levels. Genetic knockout of AnxA7 in mice significantly increases the number of implantation sites and litter sizes. Further, analysis of human endometrial biopsies showed that ANXA7 transcript and protein levels are decreased during the midluteal window of implantation in women suffering from recurrent pregnancy loss (RPL) when compared to subfertile patients. Taken together, the data indicate that ANXA7 has a conserved role in regulating endometrial receptivity and implantation.

ACS Style

Alauddin; Madhuri S. Salker; Anja T. Umbach; Janet Rajaxavier; Toshiyuki Okumura; Yogesh Singh; Anna Wagner; Sara Y. Brucker; Diethelm Wallwiener; Jan J. Brosens; Florian Lang. Annexin A7 Regulates Endometrial Receptivity. Frontiers in Cell and Developmental Biology 2020, 8, 770 .

AMA Style

Alauddin, Madhuri S. Salker, Anja T. Umbach, Janet Rajaxavier, Toshiyuki Okumura, Yogesh Singh, Anna Wagner, Sara Y. Brucker, Diethelm Wallwiener, Jan J. Brosens, Florian Lang. Annexin A7 Regulates Endometrial Receptivity. Frontiers in Cell and Developmental Biology. 2020; 8 ():770.

Chicago/Turabian Style

Alauddin; Madhuri S. Salker; Anja T. Umbach; Janet Rajaxavier; Toshiyuki Okumura; Yogesh Singh; Anna Wagner; Sara Y. Brucker; Diethelm Wallwiener; Jan J. Brosens; Florian Lang. 2020. "Annexin A7 Regulates Endometrial Receptivity." Frontiers in Cell and Developmental Biology 8, no. : 770.

Signaling and cell physiology
Published: 16 June 2020 in Pflügers Archiv - European Journal of Physiology
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Diabetes and chronic kidney disease (CKD) both trigger vascular osteogenic signaling and calcification leading to early death by cardiovascular events. Osteogenic signaling involves upregulation of the transcription factors CBFA1, MSX2, and SOX9, as well as alkaline phosphatase (ALP), an enzyme fostering calcification by degrading the calcification inhibitor pyrophosphate. In CKD, osteogenic signaling is triggered by hyperphosphatemia, which upregulates the serum and glucocorticoid-inducible kinase SGK1, a strong stimulator of the Ca2+-channel ORAI1. The channel is activated by STIM1 and accomplishes store-operated Ca2+-entry (SOCE). The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to high extracellular glucose concentrations similarly upregulates ORAI1 and/or STIM1 expression, SOCE, and osteogenic signaling. To this end, HAoSMCs were exposed to high extracellular glucose concentrations (15 mM, 24 h) without or with additional exposure to the phosphate donor ß-glycerophosphate. Transcript levels were estimated using qRT-PCR, protein abundance using Western blotting, ALP activity using a colorimetric assay kit, calcium deposits utilizing Alizarin red staining, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 μM). As a result, glucose enhanced the transcript levels of SGK1 and ORAI1, ORAI2, and STIM2, protein abundance of ORAI1, SOCE, the transcript levels of CBFA1, MSX2, SOX9, and ALPL, as well as calcium deposits. Moreover, glucose significantly augmented the stimulating effect of ß-glycerophosphate on transcript levels of SGK1 and ORAI1, SOCE, the transcript levels of osteogenic markers, as well as calcium deposits. ORAI1 inhibitor MRS1845 (10 μM) significantly blunted the glucose-induced upregulation of the CBFA1 and MSX2 transcript levels. In conclusion, the hyperglycemia of diabetes stimulates expression of SGK1 and ORAI1, thus, augmenting store-operated Ca2+-entry and osteogenic signaling in HAoSMCs.

ACS Style

Ke Ma; Basma Sukkar; Xuexue Zhu; Kuo Zhou; Hang Cao; Jakob Voelkl; Ioana Alesutan; Bernd Nürnberg; Florian Lang. Stimulation of ORAI1 expression, store-operated Ca2+ entry, and osteogenic signaling by high glucose exposure of human aortic smooth muscle cells. Pflügers Archiv - European Journal of Physiology 2020, 472, 1093 -1102.

AMA Style

Ke Ma, Basma Sukkar, Xuexue Zhu, Kuo Zhou, Hang Cao, Jakob Voelkl, Ioana Alesutan, Bernd Nürnberg, Florian Lang. Stimulation of ORAI1 expression, store-operated Ca2+ entry, and osteogenic signaling by high glucose exposure of human aortic smooth muscle cells. Pflügers Archiv - European Journal of Physiology. 2020; 472 (8):1093-1102.

Chicago/Turabian Style

Ke Ma; Basma Sukkar; Xuexue Zhu; Kuo Zhou; Hang Cao; Jakob Voelkl; Ioana Alesutan; Bernd Nürnberg; Florian Lang. 2020. "Stimulation of ORAI1 expression, store-operated Ca2+ entry, and osteogenic signaling by high glucose exposure of human aortic smooth muscle cells." Pflügers Archiv - European Journal of Physiology 472, no. 8: 1093-1102.

Invited review
Published: 11 June 2020 in Pflügers Archiv - European Journal of Physiology
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Glucose uptake into lymphocytes is accomplished by non-concentrative glucose carriers of the GLUT family (GLUT1, GLUT3, GLUT4, GLUT6) and/or by the Na+-coupled glucose carrier SGLT1. The latter accumulates glucose against glucose gradients and is still effective at very low extracellular glucose concentrations. Signaling involved in SGLT1 expression and activity includes protein kinase A (PKA), protein kinase C (PKC), serum- and glucocorticoid-inducible kinase (SGK1), AMP-activated kinase (AMPK), and Janus kinases (JAK2 and JAK3). Glucose taken up is partially stored as glycogen. In hypoxic environments, such as in tumors as well as infected and inflamed tissues, lymphocytes depend on energy production from glycogen-dependent glycolysis. The lack of SGLT1 may compromise glycogen storage and thus lymphocyte survival and function in hypoxic tissues. Accordingly, in mice, genetic knockout of sglt1 compromised bacterial clearance following Listeria monocytogenes infection leading to an invariably lethal course of the disease. Whether the effect was due to the lack of sglt1 in lymphocytes or in other cell types still remains to be determined. Clearly, additional experimental effort is required to define the role of glucose transport by GLUTs and particularly by SGLT1 for lymphocyte survival and function, as well as orchestration of the host defense against tumors and bacterial infections.

ACS Style

Florian Lang; Yogesh Singh; Madhuri Sonal Salker; Ke Ma; Aleksandra A. Pandyra; Philipp A. Lang; Karl S. Lang. Glucose transport in lymphocytes. Pflügers Archiv - European Journal of Physiology 2020, 472, 1401 -1406.

AMA Style

Florian Lang, Yogesh Singh, Madhuri Sonal Salker, Ke Ma, Aleksandra A. Pandyra, Philipp A. Lang, Karl S. Lang. Glucose transport in lymphocytes. Pflügers Archiv - European Journal of Physiology. 2020; 472 (9):1401-1406.

Chicago/Turabian Style

Florian Lang; Yogesh Singh; Madhuri Sonal Salker; Ke Ma; Aleksandra A. Pandyra; Philipp A. Lang; Karl S. Lang. 2020. "Glucose transport in lymphocytes." Pflügers Archiv - European Journal of Physiology 472, no. 9: 1401-1406.

Original article
Published: 10 June 2020 in Molecular Biology Reports
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Pyrogallol, a polyphenolic component of Acacia nilotica has previously been reported to induce apoptosis of diverse cell types. Pyrogallol is in part effective by influencing gene expression and by interference with mitochondrial function. Despite lack of nuclei and mitochondria, erythrocytes may undergo eryptosis, a suicidal death apparent from phosphatidylserine translocation to the erythrocyte surface and cell shrinkage. Eryptosis is triggered by glucose depletion, by oxidation, by hyperosmotic cell shrinkage and by excessive Ca2+ entry. As enhanced eryptosis is a common cause of anemia, uncovering inhibitors and stimulators of eryptosis may, both, be of clinical interest. Here we tested, whether eryptosis of human erythrocytes is modified by pyrogallol. Utilizing flow cytometry, phosphatidylserine abundance at the cell surface was estimated from annexin-V-binding and cell volume from forward scatter. Prior to determinations erythrocytes were incubated with or without glucose, without or with added oxidant tert-butyl-hydroperoxide (t-BOOH, 0.5 mM), without or with added hyperosmotic sucrose (550 mM) or without or with added Ca2+ ionophore ionomycin (1 µM). Treatment of erythrocytes with pyrogallol (2–8 µM) was without significant effect on annexin-V-binding and forward scatter. Glucose deprivation, t-BOOH, sucrose and ionomycin, each, triggered annexin-V-binding and decreased forward scatter. Pyrogallol significantly blunted the effects on annexin-V-binding but not on forward scatter. Pyrogallol thus blunts phosphatidylserine translocation in erythrocytes exposed to glucose depletion, oxidative stress, hyperosmotic shock and excessive Ca2+ entry.

ACS Style

Jibin Liu; Abdulla Al Mamun Bhuyan; Ke Ma; Shaqiu Zhang; Anchun Cheng; Florian Lang. Inhibition of suicidal erythrocyte death by pyrogallol. Molecular Biology Reports 2020, 47, 5025 -5032.

AMA Style

Jibin Liu, Abdulla Al Mamun Bhuyan, Ke Ma, Shaqiu Zhang, Anchun Cheng, Florian Lang. Inhibition of suicidal erythrocyte death by pyrogallol. Molecular Biology Reports. 2020; 47 (7):5025-5032.

Chicago/Turabian Style

Jibin Liu; Abdulla Al Mamun Bhuyan; Ke Ma; Shaqiu Zhang; Anchun Cheng; Florian Lang. 2020. "Inhibition of suicidal erythrocyte death by pyrogallol." Molecular Biology Reports 47, no. 7: 5025-5032.

Journal article
Published: 21 May 2020 in Scientific Reports
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Loss of function mutations of the chorein-encoding gene VPS13A lead to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with accelerated suicidal neuronal cell death, which could be reversed by lithium. Chorein upregulates the serum and glucocorticoid inducible kinase SGK1. Targets of SGK1 include the Na+/K+-ATPase, a pump required for cell survival. To explore whether chorein-deficiency affects Na+/K+ pump capacity, cortical neurons were differentiated from iPSCs generated from fibroblasts of ChAc patients and healthy volunteers. Na+/K+ pump capacity was estimated from K+-induced whole cell outward current (pump capacity). As a result, the pump capacity was completely abolished in the presence of Na+/K+ pump-inhibitor ouabain (100 µM), was significantly smaller in ChAc neurons than in control neurons, and was significantly increased in ChAc neurons by lithium treatment (24 hours 2 mM). The effect of lithium was reversed by SGK1-inhibitor GSK650394 (24 h 10 µM). Transmembrane potential (Vm) was significantly less negative in ChAc neurons than in control neurons, and was significantly increased in ChAc neurons by lithium treatment (2 mM, 24 hours). The effect of lithium on Vm was virtually abrogated by ouabain. Na+/K+ α1-subunit transcript levels and protein abundance were significantly lower in ChAc neurons than in control neurons, an effect reversed by lithium treatment (2 mM, 24 hours). In conclusion, consequences of chorein deficiency in ChAc include impaired Na+/K+ pump capacity.

ACS Style

Zohreh Hosseinzadeh; Stefan Hauser; Yogesh Singh; Lisann Pelzl; Stefanie Schuster; Yamini Sharma; Philip Höflinger; Nefeli Zacharopoulou; Christos Stournaras; Daniel L. Rathbun; Eberhart Zrenner; Ludger Schöls; Florian Lang. Decreased Na+/K+ ATPase Expression and Depolarized Cell Membrane in Neurons Differentiated from Chorea-Acanthocytosis Patients. Scientific Reports 2020, 10, 1 .

AMA Style

Zohreh Hosseinzadeh, Stefan Hauser, Yogesh Singh, Lisann Pelzl, Stefanie Schuster, Yamini Sharma, Philip Höflinger, Nefeli Zacharopoulou, Christos Stournaras, Daniel L. Rathbun, Eberhart Zrenner, Ludger Schöls, Florian Lang. Decreased Na+/K+ ATPase Expression and Depolarized Cell Membrane in Neurons Differentiated from Chorea-Acanthocytosis Patients. Scientific Reports. 2020; 10 (1):1.

Chicago/Turabian Style

Zohreh Hosseinzadeh; Stefan Hauser; Yogesh Singh; Lisann Pelzl; Stefanie Schuster; Yamini Sharma; Philip Höflinger; Nefeli Zacharopoulou; Christos Stournaras; Daniel L. Rathbun; Eberhart Zrenner; Ludger Schöls; Florian Lang. 2020. "Decreased Na+/K+ ATPase Expression and Depolarized Cell Membrane in Neurons Differentiated from Chorea-Acanthocytosis Patients." Scientific Reports 10, no. 1: 1.

Journal article
Published: 26 March 2020 in Nutrients
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Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) indicate that over 65% of adults aged 51–70 years in the U.S. do not meet hydration criteria. They have hyponatremia (serum sodium < 135 mmol/L) and/or underhydration (serum sodium >145 mmol/L, spot urine volume

ACS Style

Jodi D. Stookey; Stavros A. Kavouras; Hyungyu Suh; Florian Lang. Underhydration Is Associated with Obesity, Chronic Diseases, and Death Within 3 to 6 Years in the U.S. Population Aged 51–70 Years. Nutrients 2020, 12, 905 .

AMA Style

Jodi D. Stookey, Stavros A. Kavouras, Hyungyu Suh, Florian Lang. Underhydration Is Associated with Obesity, Chronic Diseases, and Death Within 3 to 6 Years in the U.S. Population Aged 51–70 Years. Nutrients. 2020; 12 (4):905.

Chicago/Turabian Style

Jodi D. Stookey; Stavros A. Kavouras; Hyungyu Suh; Florian Lang. 2020. "Underhydration Is Associated with Obesity, Chronic Diseases, and Death Within 3 to 6 Years in the U.S. Population Aged 51–70 Years." Nutrients 12, no. 4: 905.

Journal article
Published: 03 February 2020 in Scientific Reports
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Impairment of renal phosphate elimination in chronic kidney disease (CKD) leads to enhanced plasma and tissue phosphate concentration, which in turn up-regulates transcription factor NFAT5 and serum & glucocorticoid-inducible kinase SGK1. The kinase upregulates ORAI1, a Ca2+-channel accomplishing store-operated Ca2+-entry (SOCE). ORAI1 is stimulated following intracellular store depletion by Ca2+-sensors STIM1 and/or STIM2. In megakaryocytes and blood platelets SOCE and thus ORAI1 are powerful regulators of activity. The present study explored whether the phosphate-donor ß-glycerophosphate augments NFAT5, ORAI1,2,3 and/or STIM1,2 expressions and thus SOCE in megakaryocytes. Human megakaryocytic Meg01cells were exposed to 2 mM of phosphate-donor ß-glycerophosphate for 24 hours. Platelets were isolated from blood samples of patients with impaired kidney function or control volunteers. Transcript levels were estimated utilizing q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and SOCE from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). NFAT5 and ORAI1 protein abundance was estimated with Western blots. As a result, ß-glycerophosphate increased NFAT5, ORAI1/2/3, STIM1/2 transcript levels, as well as SOCE. Transcript levels of NFAT5, SGK1, ORAI1/2/3, and STIM1/2 as well as NFAT5 and ORAI1 protein abundance were significantly higher in platelets isolated from patients with impaired kidney function than in platelets from control volunteers. In conclusion, phosphate-donor ß-glycerophosphate triggers a signaling cascade of NFAT5/SGK1/ORAI/STIM, thus up-regulating store-operated Ca2+-entry.

ACS Style

Lisann Pelzl; Itishri Sahu; Ke Ma; David Heinzmann; Abdulla Al Mamun Bhuyan; Tamer Al-Maghout; Basma Sukkar; Yamini Sharma; Irene Marini; Flaviana Rigoni; Ferruh Artunc; Hang Cao; Ravi Gutti; Jakob Voelkl; Burkert Pieske; Meinrad Gawaz; Tamam Bakchoul; Florian Lang. Beta-Glycerophosphate-Induced ORAI1 Expression and Store Operated Ca2+ Entry in Megakaryocytes. Scientific Reports 2020, 10, 1 -11.

AMA Style

Lisann Pelzl, Itishri Sahu, Ke Ma, David Heinzmann, Abdulla Al Mamun Bhuyan, Tamer Al-Maghout, Basma Sukkar, Yamini Sharma, Irene Marini, Flaviana Rigoni, Ferruh Artunc, Hang Cao, Ravi Gutti, Jakob Voelkl, Burkert Pieske, Meinrad Gawaz, Tamam Bakchoul, Florian Lang. Beta-Glycerophosphate-Induced ORAI1 Expression and Store Operated Ca2+ Entry in Megakaryocytes. Scientific Reports. 2020; 10 (1):1-11.

Chicago/Turabian Style

Lisann Pelzl; Itishri Sahu; Ke Ma; David Heinzmann; Abdulla Al Mamun Bhuyan; Tamer Al-Maghout; Basma Sukkar; Yamini Sharma; Irene Marini; Flaviana Rigoni; Ferruh Artunc; Hang Cao; Ravi Gutti; Jakob Voelkl; Burkert Pieske; Meinrad Gawaz; Tamam Bakchoul; Florian Lang. 2020. "Beta-Glycerophosphate-Induced ORAI1 Expression and Store Operated Ca2+ Entry in Megakaryocytes." Scientific Reports 10, no. 1: 1-11.

Journal article
Published: 01 February 2020 in Biochemical and Biophysical Research Communications
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ACS Style

Xuexue Zhu; Ke Ma; Kuo Zhou; Jakob Voelkl; Ioana Alesutan; Christina Leibrock; Bernd Nürnberg; Florian Lang. Reversal of phosphate-induced ORAI1 expression, store-operated Ca2+ entry and osteogenic signaling by MgCl2 in human aortic smooth muscle cells. Biochemical and Biophysical Research Communications 2020, 523, 18 -24.

AMA Style

Xuexue Zhu, Ke Ma, Kuo Zhou, Jakob Voelkl, Ioana Alesutan, Christina Leibrock, Bernd Nürnberg, Florian Lang. Reversal of phosphate-induced ORAI1 expression, store-operated Ca2+ entry and osteogenic signaling by MgCl2 in human aortic smooth muscle cells. Biochemical and Biophysical Research Communications. 2020; 523 (1):18-24.

Chicago/Turabian Style

Xuexue Zhu; Ke Ma; Kuo Zhou; Jakob Voelkl; Ioana Alesutan; Christina Leibrock; Bernd Nürnberg; Florian Lang. 2020. "Reversal of phosphate-induced ORAI1 expression, store-operated Ca2+ entry and osteogenic signaling by MgCl2 in human aortic smooth muscle cells." Biochemical and Biophysical Research Communications 523, no. 1: 18-24.

Journal article
Published: 23 November 2019 in Neurosignals
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1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol) is a powerful regulator of mineral metabolism. The hormone increases calcium and phosphate plasma concentrations in part by stimulation of intestinal absorption and renal reabsorption of calcium and phosphate. It is primarily, but not exclusively, produced in the kidney. Renal 1,25(OH)2D3 formation is stimulated by calcium and phosphate deficiency and by parathyroid hormone which is up-regulated by hypocalcemia. 1,25(OH)2D3 formation is inhibited by fibroblast growth factor FGF23, which is up-regulated by phosphate excess and requires Klotho to become effective. Klotho- or FGF23-deficiency leads to excessive plasma 1,25(OH)2D3-, Ca2+- and phosphate-concentrations with severe soft tissue calcification and accelerated aging. Tissue calcification and premature aging are prevented by NH4Cl without affecting 1,25(OH)2D3-formation. 1,25(OH)2D3 has powerful effects apparently unrelated to mineral metabolism, including anti-inflammatory actions and modification of multiple brain functions. Excessive 1,25(OH)2D3 formation in klotho-deficient NH4Cl-treated mice leads to an amazing surge of exploratory behavior, lack of anxiety and decreased depression, effects dissipated by low vitamin D diet. Conversely, vitamin D deficient mice display reduced explorative behavior, enhanced anxiety, aberrant grooming, submissive social behavior, social neglect and maternal cannibalism. 1,25(OH)2D3 is generated in human brain, and acts on diverse structures including prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation, provides neuroprotection, down-regulates a variety of inflammatory mediators and up-regulates a wide variety of neurotrophins. Diseases postulated to be favorably modified by 1,25(OH)2D3 include multiple sclerosis, Parkinson´s disease, Alzheimer´s disease, depression, bipolar disorder and schizophrenia. Clearly, substantial additional experimentation is required to fully understand the neuro-psycho-pathophysiological role of 1,25(OH)2D3 and to exploit 1,25(OH)2D3 or related agonists in the treatment of neuro-psychiatric disorders.

ACS Style

Florian Lang; Ke Ma; Christina B. Leibrock. 1,25(OH)2D3 in Brain Function and Neuropsychiatric Disease. Neurosignals 2019, 27, 40 -49.

AMA Style

Florian Lang, Ke Ma, Christina B. Leibrock. 1,25(OH)2D3 in Brain Function and Neuropsychiatric Disease. Neurosignals. 2019; 27 (1):40-49.

Chicago/Turabian Style

Florian Lang; Ke Ma; Christina B. Leibrock. 2019. "1,25(OH)2D3 in Brain Function and Neuropsychiatric Disease." Neurosignals 27, no. 1: 40-49.

Journal article
Published: 02 October 2019 in Blood
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The investigators explore the role of PDK1 (phosphoinositide-dependent protein kinase 1) in the cytoskeletal regulation of platelet production and furnish new insights into megakaryocyte maturation and proplatelet formation.

ACS Style

Sascha Geue; Katja Aurbach; Mailin-Christin Manke; Georgi Manukjan; Patrick Münzer; David Stegner; Caroline Brähler; Britta Walker-Allgaier; Melanie Märklin; Carla Emilia Borst; Leticia Quintanilla-Fend; Dominik Rath; Tobias Geisler; Helmut Rainer Salih; Peter Seizer; Florian Lang; Bernhard Nieswandt; Meinrad Gawaz; Harald Schulze; Irina Pleines; Oliver Borst; Leticia Quintanilla-Martinez. Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis. Blood 2019, 134, 1847 -1858.

AMA Style

Sascha Geue, Katja Aurbach, Mailin-Christin Manke, Georgi Manukjan, Patrick Münzer, David Stegner, Caroline Brähler, Britta Walker-Allgaier, Melanie Märklin, Carla Emilia Borst, Leticia Quintanilla-Fend, Dominik Rath, Tobias Geisler, Helmut Rainer Salih, Peter Seizer, Florian Lang, Bernhard Nieswandt, Meinrad Gawaz, Harald Schulze, Irina Pleines, Oliver Borst, Leticia Quintanilla-Martinez. Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis. Blood. 2019; 134 (21):1847-1858.

Chicago/Turabian Style

Sascha Geue; Katja Aurbach; Mailin-Christin Manke; Georgi Manukjan; Patrick Münzer; David Stegner; Caroline Brähler; Britta Walker-Allgaier; Melanie Märklin; Carla Emilia Borst; Leticia Quintanilla-Fend; Dominik Rath; Tobias Geisler; Helmut Rainer Salih; Peter Seizer; Florian Lang; Bernhard Nieswandt; Meinrad Gawaz; Harald Schulze; Irina Pleines; Oliver Borst; Leticia Quintanilla-Martinez. 2019. "Pivotal role of PDK1 in megakaryocyte cytoskeletal dynamics and polarization during platelet biogenesis." Blood 134, no. 21: 1847-1858.

Preprint
Published: 19 September 2019
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The proper communication between gut and brain is pivotal for maintenance of health and dysregulation of the gut-brain axis can lead to several clinical disorders. Also, in Parkinson’s disease (PD) 85% of all patients experienced constipation long before showing any signs of motor phenotypes. For differential diagnosis and when it comes to preventive treatment there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperon protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 modifies the PD risk remains incompletely understood. In the present study we provide evidence that DJ-1 is implicated in shaping the gut microbiome including their metabolite production or innate immune cells (ILCs) development. We revealed that in 4 months old mice genetic deficiency of DJ-1 leads to significantly decrease in several bacterial genera and significantly increase in two specific genera, namelyAlistipesandRikenella. DJ-1 deficient mice have a higher production of calprotectin/MCP-1 inflammatory protein - a known protein involved in colonic inflammation – and significantly higher expression of glial fibrillary acidic protein (GFAP) than control littermates. Expression of a-Synuclein, a key protein in Lewy bodies, in the colon was not significantly different between genotypes. Metabolic profiles of feces extracts analysed by H1-NMR spectroscopy showed increased short chain fatty acids (SCFAs) and decreased amino acid levels, suggesting a general switch from protein towards fibre degrading strains in DJ-1 deficient mice. We observed that Malonate - which is known to influence the immune system – has significantly higher concentrations in DJ-1 deficient mice. Moreover, DJ-1 deficient mice have high levels of the phenol derivate 3-(3-Hydroxyphenyl) propanoic acid (3-HPPA) which is a breakdown product of aromatic substrates like tyrosine, phenylalanine and polyphenols. DJ-1 deficient mice also showed significantly reduced percentage of ILCs. Thus, our data suggests that absence of DJ-1 leads to increase in gut inflammatory bacteria composition, deregulated metabolites and dysregulated innate immunity which could be a key factor in the initiation of PD disease in the gut, and potentially also in brain during disease progression.

ACS Style

Yogesh Singh; Christoph Trautwein; Achal Dhariwal; Madhuri S Salker; Mohammed Alauddin; Laimdota Zigmare; Lisan Pelzl; Martina Feger; Jakob Matthes; Nicolas Casadei; Michael Föller; Vivek Pachauri; David S Park; Tak W Mak; Julia S Frick; Diethelm Wallwiener; Sara Y Brucker; Florian Lang; Olaf Riess; Laimdota Zizmare; Diethelm Wallweiner. DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs). 2019, 776005 .

AMA Style

Yogesh Singh, Christoph Trautwein, Achal Dhariwal, Madhuri S Salker, Mohammed Alauddin, Laimdota Zigmare, Lisan Pelzl, Martina Feger, Jakob Matthes, Nicolas Casadei, Michael Föller, Vivek Pachauri, David S Park, Tak W Mak, Julia S Frick, Diethelm Wallwiener, Sara Y Brucker, Florian Lang, Olaf Riess, Laimdota Zizmare, Diethelm Wallweiner. DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs). . 2019; ():776005.

Chicago/Turabian Style

Yogesh Singh; Christoph Trautwein; Achal Dhariwal; Madhuri S Salker; Mohammed Alauddin; Laimdota Zigmare; Lisan Pelzl; Martina Feger; Jakob Matthes; Nicolas Casadei; Michael Föller; Vivek Pachauri; David S Park; Tak W Mak; Julia S Frick; Diethelm Wallwiener; Sara Y Brucker; Florian Lang; Olaf Riess; Laimdota Zizmare; Diethelm Wallweiner. 2019. "DJ-1 (Park7) affects the gut microbiome, metabolites and development of Innate Lymphoid cells (ILCs)." , no. : 776005.

Journal article
Published: 07 September 2019 in Cellular Signalling
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Elevated transforming growth factor β1 (TGFβ1) levels are frequently observed in chronic kidney disease (CKD) patients. TGFβ1 contributes to development of medial vascular calcification during hyperphosphatemia, a pathological process promoted by osteo−/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Vasorin is a transmembrane glycoprotein highly expressed in VSMCs, which is able to bind TGFβ to inhibit TGFβ signaling. Thus, the present study explored the effects of vasorin on osteo−/chondrogenic transdifferentiation and calcification of VSMCs. Primary human aortic smooth muscle cells (HAoSMCs) were treated with recombinant human TGFβ1 or β-glycerophosphate without or with recombinant human vasorin or vasorin gene silencing by siRNA. As a result, TGFβ1 down-regulated vasorin mRNA expression in HAoSMCs. Vasorin supplementation inhibited TGFβ1-induced pathway activation, SMAD2 phosphorylation and downstream target genes expression in HAoSMCs. Furthermore, treatment with exogenous vasorin blunted, while vasorin knockdown augmented TGFβ1-induced osteo−/chondrogenic transdifferentiation of HAoSMCs. In addition, phosphate down-regulated vasorin mRNA expression in HAoSMCs. Phosphate-induced TGFβ1 expression was not affected by addition of exogenous vasorin. Nonetheless, the phosphate-induced TGFβ1 signaling, osteo−/chondrogenic transdifferentiation and calcification of HAoSMCs were all blunted by vasorin. Conversely, silencing of vasorin aggravated osteoinduction in HAoSMCs during high phosphate conditions. Aortic vasorin expression was reduced in the hyperphosphatemic klotho-hypomorphic mouse model of CKD-related vascular calcification. In conclusion, vasorin, which suppresses TGFβ1 signaling and protects against osteo−/chondrogenic transdifferentiation and calcification of VSMCs, is reduced by pro-calcifying conditions. Thus, vasorin is a novel key regulator of VSMC calcification and may represent a potential therapeutic target for vascular calcification during CKD.

ACS Style

Trang T.D. Luong; Misael Estepa; Beate Boehme; Burkert Pieske; Florian Lang; Kai-Uwe Eckardt; Jakob Voelkl; Ioana Alesutan. Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling. Cellular Signalling 2019, 64, 109414 .

AMA Style

Trang T.D. Luong, Misael Estepa, Beate Boehme, Burkert Pieske, Florian Lang, Kai-Uwe Eckardt, Jakob Voelkl, Ioana Alesutan. Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling. Cellular Signalling. 2019; 64 ():109414.

Chicago/Turabian Style

Trang T.D. Luong; Misael Estepa; Beate Boehme; Burkert Pieske; Florian Lang; Kai-Uwe Eckardt; Jakob Voelkl; Ioana Alesutan. 2019. "Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling." Cellular Signalling 64, no. : 109414.