Article
Cell Biology
Tobias A. Weber, Johan Lundkvist, Johanna Wanngren, Hlin Kvartsberg, ShaoBo Jin, Pia Larssen, Dan Wu, Daniel Oliveira, Karolina Minta, Gunnar Brinkmalm, Henrik Zetterberg, Kaj Blennow, Gunnar Nordvall, Bengt Winblad, Erik Portelius, Helena Karlstrom
Summary: The study demonstrates that gamma-secretase modulators selectively affect the production of Aβ, with a particular modulation on the Aβ-like proteins derived from EphA4.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2022)
Article
Neurosciences
Masato Maesako, Mei C. Q. Houser, Yuliia Turchyna, Michael S. Wolfe, Oksana Berezovska
Summary: In this study, we used a novel imaging method to visualize the subcellular compartment where γ-secretase primarily cleaves C99 to generate Aβ in mouse cortical neurons. Our findings suggest that γ-secretase processes C99 mainly in low-pH compartments and Aβ is accumulated in the same subcellular loci. Additionally, we found a functional correlation between endo-lysosomal pH and cellular γ-secretase activity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Agata Tarkowska, Wanda Furmaga-Jablonska, Jacek Bogucki, Janusz Kocki, Ryszard Pluta
Summary: Researchers found that after perinatal asphyxia, key genes related to neurodegeneration showed decreased expression in neonatal lymphocytes, while the expression of presenilin 1 and 2 genes varied at different time points. This could potentially serve as biomarkers for evaluating the severity of neurodegeneration and determining the timing of its occurrence.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Hirotaka Watanabe, Kent Imaizumi, Tetsuo Cai, Zhi Zhou, Taisuke Tomita, Hideyuki Okano
Summary: Genetic mutations in presenilin genes (PS1, PS2) are associated with familial Alzheimer's disease (AD). This study investigated the physiological roles of PS in human neurons using iPSCs and generated PS-null human cortical neurons. PS was found to play essential roles in Notch signaling and Aβ production, with PS1 and PS2 showing different effects on cleavage of different substrates.
Review
Immunology
Jinwei Zhang, Xiaoqian Wu, Jideng Ma, Keren Long, Jing Sun, Mingzhou Li, Liangpeng Ge
Summary: Hypoxia and HIF signaling have important regulatory roles in cell biology, but their role in B cell biology is still controversial. Studies have found that hypoxia niches exist in different developmental stages of B cells, suggesting that hypoxia and HIF signaling may play a crucial role in the development, metabolism, and function of B cells. A better understanding of the role of hypoxia in B cell-mediated adaptive immunity could provide new strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Siling Liu, Zhongyu Zhang, Lianwei Li, Li Yao, Zhanshan Ma, Jiali Li
Summary: PTPRT is downregulated in the brains of AD patients and mouse models, and its cleavage releases PICD which translocates to the nucleus and inhibits pSTAT3 accumulation, leading to neuronal cell death. Overexpression of PICD affects gene expression related to synapse formation, cell adhesion, and protein dephosphorylation. Furthermore, PICD overexpression improves synaptic function, reduces phospho-STAT3(Y705) and amyloid beta production in APP/PS1 mice, and partially rescues behavioral deficits.
Review
Pharmacology & Pharmacy
Baoqi Yu, Xia Wang, Yanting Song, Guomin Xie, Shiyu Jiao, Li Shi, Xuejie Cao, Xinyao Han, Aijuan Qu
Summary: Cardiovascular diseases are the leading cause of death worldwide, and hypoxia-inducible factors (HIFs) play an important role in their pathogenesis. Recent studies have revealed the role of cell-specific HIFs in various cardiovascular diseases, but the potential clinical application of HIF inhibitors in the treatment of cardiovascular diseases is not well understood.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Urszula Orzel, Pawel Pasznik, Przemyslaw Miszta, Marcin Lorkowski, Szymon Niewieczerzal, Jakub Jakowiecki, Slawomir Filipek
Summary: Despite advances in research on Alzheimer's disease, its mechanism is still not fully understood. The GS-SMD server allows cleaving and unfolding of all known GS substrates to study the mechanism of substrate unfolding and the role of mutations. This server provides quick simulations in an implicit water-membrane environment and allows visualization, analysis, and comparison of multiple simulations.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Takahito Maki, Masahito Sawahata, Ichiro Akutsu, Shohei Amaike, Genki Hiramatsu, Daisuke Uta, Naotaka Izuo, Takahiko Shimizu, Kazuhiro Irie, Toshiaki Kume
Summary: This study evaluated phenotypic changes in AD mice models, revealing the crucial role of toxic Aβ conformers in AD pathology, leading to dysregulation of HIF proteins, affecting cognitive function and neuronal changes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Courtney Alexander, Thomas Li, Yorito Hattori, Danica Chiu, Georgia R. Frost, Lauren Jonas, Chenge Liu, Corey J. Anderson, Eitan Wong, Laibaik Park, Costantino Iadecola, Yue-Ming Li
Summary: Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase to promote amyloid-beta production in hypoxic-ischemic conditions, leading to increased risk for Alzheimer's disease (AD).
MOLECULAR PSYCHIATRY
(2022)
Review
Pharmacology & Pharmacy
Jie Lun, Hongwei Zhang, Jing Guo, Mengchao Yu, Jing Fang
Summary: Inflammatory bowel disease (IBD) is a chronic disease characterized by intestinal inflammation. Hypoxia-inducible factor (HIF) is induced in response to hypoxia and plays a role in protecting the intestinal barrier. Stabilization of HIF through inhibition of prolyl hydroxylases (PHDs) is a potential therapeutic strategy for IBD treatment. This review discusses the role of HIF and PHDs in IBD and the therapeutic potential of targeting the PHD-HIF pathway.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Cell Biology
Bo Zhang, Yan Chen, Lei Bao, Weibo Luo
Summary: This study demonstrates that hypoxia upregulates the expression of GPT2 in GBM cells through HIF-2 activation. GPT2 is localized in the nucleus and mitochondria and can decrease α-ketoglutarate levels in GBM cells. Inhibition of GPT2 can reduce GBM cell growth and migration, and knockout of GPT2 inhibits GBM tumor growth in mice.
Review
Cell Biology
Elena V. Mitroshina, Maria O. Savyuk, Evgeni Ponimaskin, Maria V. Vedunova
Summary: Hypoxia is a common pathological condition induced by various events, with the body's adaptation to it being crucial for health and disease. HIFs, a family of transcription factors, play a key role in cellular responses to hypoxia and are increasingly viewed as potential targets for treating a range of hypoxia-associated diseases. The role of HIFs in adaptation to hypoxia is universal across tissue types, including the CNS, where they are involved in regulating neurogenesis, nerve cell differentiation, and neuronal apoptosis, potentially offering new therapeutic opportunities.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Biology
Corine M. van der Weele, William R. Jeffery
Summary: Dark caves lacking primary productivity expose subterranean animals to hypoxia. Cavefish cope with hypoxia by increasing erythrocyte development and constitutive hif1 gene overexpression.
Article
Chemistry, Physical
Jose-Luis Velasco-Bolom, Laura Dominguez
Summary: The study utilizing molecular dynamics simulations and network analysis revealed the dynamic behavior of γ-secretase in its apo form and bound to different substrates, highlighting the crucial role of the NCT-lobule in communication and dynamics. Systems with long extracellular substrates, such as APP-C99 and Notch, preferred compact conformations.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Letter
Hematology
Tanguy Corre, Belen Ponte, Edward Pivin, Menno Pruijm, Daniel Ackermann, Georg Ehret, Katharina Spanaus, Murielle Bochud, Roland H. Wenger
Article
Physiology
Sophie L. Dahl, Svende Pfundstein, Rico Hunkeler, Xingtong Dong, Thomas Knoepfel, Patrick Spielmann, Carsten C. Scholz, Karen A. Nolan, Roland H. Wenger
Summary: Fibroblast-like renal erythropoietin (Epo) producing (REP) cells respond to tissue hypoxia and play a role in erythropoiesis. However, during fibrotic tissue remodelling, Epo expression is inhibited. This study found that REP cells do not die, proliferate, migrate, or differentiate into myofibroblasts. Instead, there is a transient repression of Epo transcription. Additionally, REP cells can be repeatedly recruited by tissue hypoxia, and a pharmacological hypoxia-inducible factor (HIF) stabilizer can rescue dormant REP cells and restore Epo expression. These findings demonstrate the persistence and functionality of REP cells during Epo suppression.
Review
Biochemistry & Molecular Biology
Yulia L. Volkova, Christina Pickel, Agnieszka E. Jucht, Roland H. Wenger, Carsten C. Scholz
Summary: The cellular oxygen sensor factor FIH plays a vital role in monitoring oxygen availability and regulating cellular responses. It has been found to have diverse enzymatic activities and substrates outside the hypoxia-inducible factor pathway. Understanding the physiological functions and potential therapeutic implications of FIH requires further investigation.
ANTIOXIDANTS & REDOX SIGNALING
(2022)
Article
Biochemistry & Molecular Biology
Amalia Ruiz-Serrano, Christina N. Boyle, Josep M. Monne Rodriguez, Julia Guenter, Agnieszka E. Jucht, Svende Pfundstein, Andreas M. Bapst, Thomas A. Lutz, Roland H. Wenger, Carsten C. Scholz
Summary: Dysregulated energy metabolism is a major cause of various diseases. OTUB1 plays an important regulatory role in energy metabolism. Deletion of OTUB1 in mice leads to increased energy expenditure and improved glucose metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Andreas M. Bapst, Thomas Knopfel, Karen A. Nolan, Faik Imeri, Claus D. Schuh, Andrew M. Hall, Jia Guo, Doerthe M. Katschinski, Roland H. Wenger
Summary: The kidney is the main source of erythropoietin (EPO) in circulating red blood cell production in adult mammals. In this study using a transgenic mouse model, multiple subtypes of renal EPO-producing (REP) cells were identified. Under nonpermissive conditions, REP-derived (REPD) cells stopped proliferating and acquired a stem cell-like state. These cells maintained the on-off nature of EPO expression observed in REP cells and exhibited myofibroblastic signaling. In vitro cultured REPD cells generated long nanotubes that aligned with blood vessels and increased in number under hypoxic conditions. Apart from pericytes, REPD cells readily differentiated into neuroglia but not adipogenic, chondrogenic, or osteogenic lineages.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Cell Biology
Aline Jatho, Anke Zieseniss, Katja Brechtel-Curth, Jia Guo, Kai Oliver Boeker, Gabriela Salinas, Roland H. Wenger, Doerthe M. Katschinski
Summary: The anti-anemia drug roxadustat stabilizes HIFalpha and stimulates Epo synthesis by inhibiting the PHD enzymes. The study found that roxadustat treatment increased the number of Sca-1(+) mesenchymal cells in the kidneys, which exhibited characteristics of MSC-like cells and were capable of producing Epo under hypoxic conditions.
Article
Biochemistry & Molecular Biology
Redona Hafizi, Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Stephanie Schwalm, Sandra Trautmann, Roland H. Wenger, Josef Pfeilschifter, Andrea Huwiler
Summary: The study demonstrated that sphingolipids have diverse effects on Epo synthesis, with accumulation of intracellular Sph reducing Epo synthesis, while iS1P enhanced Epo synthesis through S1P(1+3) receptors. Selective inhibition of Sphk2 appears to be a promising approach to increase Epo synthesis and reduce anemia development in chronic kidney disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Physiology
Sophie L. Dahl, Andreas M. Bapst, Stellor Nlandu Khodo, Carsten C. Scholz, Roland H. Wenger
Summary: Renal erythropoietin-producing (REP) cells are a rare and poorly understood cell type that transiently produces Epo mRNA under hypoxic conditions. REP cells lose their identity and Epo production after in vitro culture, similar to what happens during tissue remodeling in chronic kidney disease. Transgenic mouse models have been developed to label and study REP cells, and future single-cell analysis will provide insights into the regulation of Epo expression in this cell type.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2022)
Article
Biology
Anna Keppner, Miguel Correia, Sara Santambrogio, Teng Wei Koay, Darko Maric, Carina Osterhof, Denise Winter, Angele Clerc, Michael Stumpe, Frederic Chalmel, Sylvia Dewilde, Alex Odermatt, Dieter Kressler, Thomas Hankeln, Roland H. Wenger, David Hoogewijs
Summary: Spermatogenesis relies on the gene expression program driven by Adgb, where the absence of Adgb leads to male infertility and abnormal sperm shape. Adgb interacts with Sept10, and the absence of Adgb mislocalizes Sept10 in sperm, revealing the importance of Adgb in proper sperm head shaping and flagellum formation.
Article
Biochemistry & Molecular Biology
Wenyu Wu Klingler, Nadine Giger, Lukas Schneider, Vipin Babu, Christiane Konig, Patrick Spielmann, Roland H. Wenger, Stefano Ferrari, Bernhard Spingler
Summary: This study reports the design of short PEG chain functionalized Pc photosensitizers to decrease aggregation and increase aqueous solubility. The best-performing photosensitizer, MLC31, showed high photocytotoxicity and mitochondrial targeting under near-infrared light, making it a potential candidate for cisplatin-resistant cancer cell therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Bjort K. Kragesteen, Amir Giladi, Eyal David, Shahar Halevi, Laufey Geirsdottir, Olga M. Lempke, Baoguo Li, Andreas M. Bapst, Ken Xie, Yonatan Katzenelenbogen, Sophie L. Dahl, Fadi Sheban, Anna Gurevich-Shapiro, Mor Zada, Truong San Phan, Roberto Avellino, Shuang-Yin Wang, Oren Barboy, Shir Shlomi-Loubaton, Sandra Winning, Philipp P. Markwerth, Snir Dekalo, Hadas Keren-Shaul, Merav Kedmi, Martin Sikora, Joachim Fandrey, Thorfinn S. Korneliussen, Josef T. Prchal, Barak Rosenzweig, Vladimir Yutkin, Fernando Racimo, Eske Willerslev, Chamutal Gur, Roland H. Wenger, Ido Amit
Summary: Single-cell RNA and transposase-accessible chromatin (ATAC) sequencing in a mouse model identified a rare cell subset called Norn cells in kidney stroma as the major source of endocrine Epo production in mice, and this finding was confirmed in human kidney tissues. These findings provide new insights into EPO gene regulation and may lead to improved therapies for anemia.
Article
Multidisciplinary Sciences
Merve Kayhan, Judith Vouillamoz, Dayme Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A. Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H. Wenger, Stellor Nlandu Khodo
Summary: Excessive TGF-beta signaling and mitochondrial dysfunction contribute to the progression of chronic kidney disease (CKD). This study investigates the role of TGF-beta signaling in proximal tubule (PT) mitochondria dysfunction and inflammation in CKD. The findings suggest potential therapeutic targets to mitigate CKD progression.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Willy Kuo, Diego Rossinelli, Georg Schulz, Roland H. Wenger, Simone Hieber, Bert Muller, Vartan Kurtcuoglu
Summary: The performance of machine learning algorithms in segmenting 3D biomedical images falls short of expectations compared to 2D photos. This is due to the lack of large, high-quality training datasets. The HR-Kidney dataset presented in this work provides a solution by offering a significantly larger dataset and can be used to further advance image processing, data augmentation, and machine learning research.
Meeting Abstract
Physiology
D. Maric, A. Keppner, M. Correia, M. Chantillon, L. Yerly, I. A. Scerri, T. Sidibe, L. Monney, I. M. C. Orlando, T. Corre, M. Bochud, A. Odermatt, R. H. Wenger, B. Gardie, H. Cario, D. Hoogewijs
Meeting Abstract
Physiology
S. M. Burger, M. Wilk, T. Knopfel, R. H. Wenger