Article
Pharmacology & Pharmacy
Linlin Fan, Hao Liu, Guofu Zhu, Shekhar Singh, Ze Yu, Shumin Wang, Hong Luo, Shiying Liu, Yawei Xu, Junbo Ge, Dongyang Jiang, Jinjiang Pang
Summary: This study reveals the critical role of CASP4/11 in adult angiogenesis and provides a promising therapeutic target for angiogenesis-related diseases in the future.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Cell Biology
Lizhen Liu, Peng Deng, Sailan Liu, Jing Han Hong, Rong Xiao, Peiyong Guan, Yali Wang, Peili Wang, Jiuping Gao, Jinghong Chen, Yichen Sun, Jianfeng Chen, Hai-Qiang Mai, Jing Tan
Summary: Through transcriptomic profiling analysis of 23 tumor tissues, it was found that NOTCH3 was highly expressed in chemoresistance nasopharyngeal carcinoma (NPC) patients, and its overexpression was associated with poor clinical outcome. Mechanistically, enhancer remodeling was shown to drive the aberrant hyperactivation of NOTCH3 in chemoresistant NPC. Notably, NOTCH3 was found to upregulate SLUG to induce chemo-resistance of NPC cells, and higher expression of SLUG was associated with poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 enhanced chemosensitivity of NPC in vitro, while overexpression of NOTCH3 increased chemoresistance of NPC in vivo. Targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC.
CELL DEATH & DISEASE
(2023)
Editorial Material
Biochemistry & Molecular Biology
Daniel R. Dries, Gang Yu
Summary: Research showed that gamma-secretase is a potential therapeutic target for Alzheimer's disease, and provided new opportunities for treatment.
Article
Cell Biology
Juliann B. Tefft, Jennifer L. Bays, Alex Lammers, Sudong Kim, Jeroen Eyckmans, Christopher S. Chen
Summary: The interplay between NOTCH1 and NOTCH3 is crucial for pericyte-induced vascular stabilization, as both components are required for the proper formation and function of the endothelium.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Congkuan Song, Jinjin Zhang, Chenzhen Xu, Minglang Gao, Ning Li, Qing Geng
Summary: This article discusses the potential and problems of gamma-secretase and its inhibitors in cancer treatment, introducing gamma-secretase as a multi-substrate enzyme and its important role in cellular activities. The failure of current GSIs in clinical trials may be attributed to various factors.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Dieter Petit, Manuel Hitzenberger, Matthias Koch, Sam Lismont, Katarzyna Marta Zoltowska, Thomas Enzlein, Carsten Hopf, Martin Zacharias, Lucia Chavez-Gutierrez
Summary: This study investigates the interactions between an imidazole-based GSM and its target gamma-secretase-APP, and reveals that a part of the modulator interacts with a binding site on gamma-secretase, triggering rearrangements and stabilizing enzyme-substrate interactions.
Article
Oncology
Annamil Alvarez-Trotta, William Guerrant, Luisana Astudillo, Mohini Lahiry, Giulia Diluvio, Elena Shersher, Hugo Kaneku, David J. Robbins, Darren Orton, Anthony J. Capobianco
Summary: NADI-351 is the first specific small-molecule inhibitor that selectively disrupts Notch1 transcriptional complexes, demonstrating robust antitumor activity without inducing intestinal toxicity, providing a potential therapeutic approach for improved cancer treatment.
Article
Biochemistry & Molecular Biology
Matthias Koch, Thomas Enzlein, Shu-Yu Chen, Dieter Petit, Sam Lismont, Martin Zacharias, Carsten Hopf, Lucia Chavez-Gutierrez
Summary: This study explores the mechanism that controls the processing of the amyloid precursor protein (APP) by gamma-secretases, which is crucial in determining the length of amyloid-beta (A beta) peptides and their role in Alzheimer's disease (AD) pathogenesis. The researchers found that polar interactions established by the APPC99 ectodomain (ECD) play a key role in regulating the cleavage of APP by gamma-secretases. Increasing the hydrophobicity of APPC99-ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associated pathogenic gamma-secretase and APP variants on A beta length. Furthermore, the study reveals that APPC99-ECD facilitates the production of longer A beta peptides caused by certain gamma-secretase inhibitors. These findings highlight the importance of the APPC99-ECD in regulating gamma-secretase activity and suggest it as a potential target for developing compounds that can selectively promote APP processing by these enzymes.
Article
Oncology
Shinsuke Suzuki, Sawako Hourai, Kimiharu Uozumi, Yuichirou Uchida, Makoto Yoshimitsu, Hachiman Miho, Naomichi Arima, Shin-Ichi Ueno, Kenji Ishitsuka
Summary: This study reveals that NOTCH1 protein is constitutively activated but likely a passenger in NOTCH1-mutation-negative ATL cell proliferation. Furthermore, GSI does not suppress the growth of ATL cell lines.
Article
Biochemistry & Molecular Biology
Wei Kang, Jinglin Zhang, Tingting Huang, Yuhang Zhou, Chi Chun Wong, Ronald C. K. Chan, Yujuan Dong, Feng Wu, Bin Zhang, William K. K. Wu, Michael W. Y. Chan, Alfred S. L. Cheng, Jun Yu, Nathalie Wong, Kwok Wai Lo, Ka Fai To
Summary: Aberrant activation of NOTCH3 has been linked to poor clinical outcomes in gastric cancer, partially attributed to the silencing of tumor suppressor miRNAs miR-491-5p and miR-875-5p. PHLDB2 was identified as a functional downstream modulator of NOTCH3 in gastric carcinogenesis, with positive correlation with NOTCH3 and negative correlation with miR-491-5p. The NOTCH3-PHLDB2-Akt cascade acts oncogenically in gastric carcinogenesis and may serve as a potential therapeutic target.
Article
Multidisciplinary Sciences
Chen Jin, Jiaoni Wang, Yumeng Wang, Bojun Jia, Xuefei Guo, Guanghui Yang, Peng Xu, Paul Greengard, Rui Zhou, Yigong Shi
Summary: In this study, researchers discovered that GSAP-16K can modulate the cleavage of APP by gamma-secretase through both dilute phase and condensate formation. The dilute phase of GSAP-16K promotes the production of Aβ42, while the condensates of GSAP-16K reduce the cleavage of APP-C99. Additionally, GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings provide mechanistic insights into the modulation of gamma-secretase activity and have implications for the development of potential therapeutics for diseases like Alzheimer's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Jiachen Wen, Dan Liu, Linxiang Zhao
Summary: Gamma-secretase is a large transmembrane protein complex consisting of four distinct units, which has garnered attention for its role in intramembrane proteolysis. The recent discovery of its atomic structure through cryo-EM has enhanced our understanding of its physiological functions and facilitated the development of novel molecules targeting gamma-secretase. This review focuses on the latest progress of gamma-secretase inhibitors and modulators in clinical and preclinical stages, as well as their potential applications in various biological indications.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Neurosciences
Gunnar Nordvall, Johan Lundkvist, Johan Sandin
Summary: Recent clinical data have shown that removing A beta-amyloid plaques in early Alzheimer's disease can slow down disease progression. This progress validates the amyloid cascade hypothesis and highlights the importance of targeting A beta-amyloid for therapeutic purposes. It also suggests that reducing the production of amyloidogenic A beta can prevent the formation of A beta-pathology. Further research is needed to explore the potential of gamma-secretase modulators in preventing and treating Alzheimer's disease.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Meewhi Kim, Ilya Bezprozvanny
Summary: Proteolytic processing of amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease (AD). Mutations in APP, PS1, or PS2 affect APP proteolysis by gamma-secretase and influence the levels of A beta 40 and A beta 42 peptides. This paper proposes a mechanistic hypothesis that may reconcile conflicting ideas and observations regarding the role of A beta peptides and gamma-secretase in AD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Microbiology
Isha Pahuja, Kriti Negi, Anjna Kumari, Meetu Agarwal, Suparba Mukhopadhyay, Babu Mathew, Shivam Chaturvedi, Jaswinder Singh Maras, Ashima Bhaskar, Ved Prakash Dwivedi
Summary: Berberine (BBR) enhances host defense mechanisms against Mycobacterium tuberculosis (M.tb) and stimulates the differentiation and expansion of specific effector memory T cells, leading to improved protection against tuberculosis (TB) infection.