Article
Immunology
Lindsay E. Nyhoff, Amber S. Griffith, Emily S. Clark, James W. Thomas, Wasif N. Khan, Peggy L. Kendall
Summary: Bruton's tyrosine kinase (Btk) plays a crucial role in inhibiting the development of mature anti-insulin B cells, removal of Btk affects the functions of anti-insulin B cells in terms of protein expression, proliferation, etc.
JOURNAL OF IMMUNOLOGY
(2021)
Article
Chemistry, Medicinal
Junli Huang, Zeli Ma, Zichao Yang, Zengzhu He, Jingna Bao, Xiaopeng Peng, Yao Liu, Ting Chen, Shumin Cai, Jianjun Chen, Zhenhua Zeng
Summary: In this study, a novel series of Ibrutinib-based BTK PROTACs were designed, synthesized, and analyzed for their structure-activity relationship. Compound 15 showed the most potent degrading activity, with a DC50 of 3.18 nM, which was significantly better than the positive control MT802 (DC50 of 63.31 nM). Compound 15 could degrade BTK protein in LPS-stimulated cells and inhibit the activation of NF-kappaB, leading to reduced expression and secretion of proinflammatory cytokines. Additionally, compound 15 demonstrated anti-inflammatory effects in a mouse peritonitis model. Overall, this study highlights the potential of targeting BTK degradation as a therapeutic strategy for inflammatory disorders, and compound 15 represents a promising lead compound for further development as an anti-inflammatory agent.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Hematology
Ye Seul Lim, Sun-Mi Yoo, Vineet Patil, Han Wool Kim, Hyun-Hwi Kim, Beomseon Suh, Ji Youn Park, Na-rae Jeong, Chi Hoon Park, Je Ho Ryu, Byung-Hoon Lee, Pilho Kim, Song Hee Lee
Summary: This study developed a potent PROTACs targeting BTK to inhibit BCR signaling and block the development of B-cell lymphomas. The results showed that UBX-382 exhibited strong degradation activity against both WT and mutant BTK proteins in vitro and in vivo, effectively inhibiting tumor growth in murine xenograft models. Additionally, UBX-382 selectively induced degradation of protein signaling pathways in various hematological cancer cells. These findings suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.
Article
Immunology
Kunihiko Moriya, Tomohiro Nakano, Yoshitaka Honda, Miyuki Tsumura, Masato Ogishi, Motoshi Sonoda, Masahiko Nishitani-Isa, Takashi Uchida, Mohamed Hbibi, Yoko Mizoguchi, Masataka Ishimura, Kazushi Izawa, Takaki Asano, Fumihiko Kakuta, Daiki Abukawa, Darawan Rinchai, Peng Zhang, Naotomo Kambe, Aziz Bousfiha, Takahiro Yasumi, Bertrand Boisson, Anne Puel, Jean-Laurent Casanova, Ryuta Nishikomori, Shouichi Ohga, Satoshi Okada, Yoji Sasahara, Shigeo Kure
Summary: This study reports six patients from five families with RELA mutations, leading to autoinflammatory and autoimmune manifestations. The mutations result in loss of function of RelA protein, leading to excessive IFN expression and autoimmune response. The DN RELA mutations are identified as a novel cause of chronic mucocutaneous ulcerations with autoinflammatory and autoimmune manifestations.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Chemistry, Medicinal
Brian T. Hopkins, Eris Bame, Bekim Bajrami, Cheryl Black, Tonika Bohnert, Carrie Boiselle, Doug Burdette, Jeremy C. Burns, Luisette Delva, Douglas Donaldson, Richard Grater, Chungang Gu, Marc Hoemberger, Josh Johnson, Sudarshan Kapadnis, Kris King, Mukesh Lulla, Bin Ma, Isaac Marx, Tom Magee, Robert Meissner, Claire M. Metrick, Michael Mingueneau, Paramasivam Murugan, Kevin L. Otipoby, Evelyne Polack, Urjana Poreci, Robin Prince, Allie M. Roach, Chris Rowbottom, Joseph C. Santoro, Patricia Schroeder, Hao Tang, Eric Tien, Fengmei Zhang, Joseph Lyssikatos
Summary: Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder that leads to permanent disability. The discovery of BIIB091 as a selective, reversible drug provides a potential treatment option for MS.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Zuoxiang Xiao, Gongping Shi, Sichuan Xi, Amit Kumar Singh, Jami Willette-Brown, Xin Li, Feng Zhu, Ling Su, Xiaolin Wu, David S. Schrump, Yinling Hu
Summary: This study found that the overexpressed TNFR1-UBCH10 axis promotes lung cancer development and metastasis through a dedifferentiation mechanism in human lung squamous cell carcinoma (SCC). These findings provide potential targets for the development of differentiation-related therapies for lung SCC.
CELL DEATH & DISEASE
(2022)
Article
Multidisciplinary Sciences
Shusei Sugiyama, Kohdai Yamada, Miwako Denda, Satoshi Yamanaka, Satoshi Ozawa, Ryo Morishita, Tatsuya Sawasaki
Summary: Protein-protein interaction analysis is crucial for understanding protein functions. Researchers have developed a cell-free protein array technology, CF-PPiD, which uses proximity biotinylation to identify specific interacting proteins. This method allows for the biochemical identification and validation of protein interactions in cells.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Chao Zhu, Wei Chen, Haiming Cui, Zhigang Huang, Ru Ding, Na Li, Qinqin Wang, Feng Wu, Yanmin Zhao, Xiaoliang Cong
Summary: Oxidized low-density lipoprotein (ox-LDL) promotes the expression of TRIM64, enhancing the activation of NLRP3 inflammasomes and the expression of downstream molecules. TRIM64 interacts with I kappa B alpha, promoting I kappa B alpha ubiquitination to activate the NF-kappa B signaling pathway. TRIM64 and NF-kappa B form a positive feedback mechanism in the development of atherosclerosis.
CELL BIOLOGY AND TOXICOLOGY
(2023)
Article
Multidisciplinary Sciences
Chun-Hao Chang, Yun-Li Lin, Yeu-Sheng Tyan, Yun-Hsuan Chiu, Ya-Han Liang, Chie-Pein Chen, Jiahn-Chun Wu, Hwai-Shi Wang
Summary: Human umbilical cord Wharton's jelly derived mesenchymal stem cells (hUCMSCs) have the ability to migrate to damaged sites in response to signals. IL-1 beta induces the expression of MMP-3 in hUCMSCs, which is related to cell migration. Additionally, ERK1/2, JNK, p38 MAPK and Akt signaling pathways are involved in IL-1 beta-induced hUCMSCs migration through MMP-3 expression.
Article
Immunology
Jichun Lin, Wenshuo Fang, Zhuo Xiang, Qingqing Wang, Huapeng Cheng, Shimin Chen, Jing Fang, Jia Liu, Qiang Wang, Zhimin Lu, Leina Ma
Summary: It has been found that glycolytic enzyme hexokinase 2 (HK2) plays a crucial role in upregulating PD-L1 expression in breast cancer cells. Under high glucose conditions, HK2 acts as a protein kinase and phosphorylates IκBa at T291, leading to the degradation of IκBa and activation of NF-κB, resulting in the promotion of PD-L1 expression. Correlation analysis shows that HK2 and PD-L1 expression levels are positively correlated with immune cell infiltration and survival time of breast cancer patients. These findings highlight the potential of targeting the protein kinase activity of HK2 for breast cancer treatment.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Medicine, Research & Experimental
Huimin Qiao, Zhuofeng Mao, Wei Wang, Xin Chen, Suhuan Wang, Haolong Fan, Tianyi Zhao, Huiqing Hou, Mei Dong
Summary: This study analyzed the changes in the BTK/NF-kappa B pathway and related chemokines in the cerebrospinal fluid and peripheral blood samples of patients with NMOSD in different stages. The results showed that these factors were significantly higher in the NMOSD group in both the acute and remission phase compared to the control group. The study revealed the important role of the BTK/NF-kappa B pathway in the progression of NMOSD pathology and provided evidence for its potential as a therapeutic target.
EUROPEAN JOURNAL OF MEDICAL RESEARCH
(2022)
Review
Health Care Sciences & Services
Katharine L. Lewis, Chan Y. Cheah
Summary: The B-cell receptor signalling pathway is crucial in the development of B-cell malignancies, with Bruton's tyrosine kinase (BTK) activation as a central element. While covalent BTK inhibitors have revolutionized treatment, issues such as adverse events and resistance have led to the exploration of non-covalent BTK inhibitors as an alternative therapeutic option. These non-covalent BTK inhibitors offer promise for patients intolerant to or experiencing disease progression with traditional covalent BTK inhibitors.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Cell Biology
Lucy Penfold, Angela Woods, Alice E. Pollard, Julia Arizanova, Eneko Pascual-Navarro, Phillip J. Muckett, Marian H. Dore, Alex Montoya, Chad Whilding, Louise Fets, Joao Mokochinski, Theodora A. Constantin, Anabel Varela-Carver, Damien A. Leach, Charlotte L. Bevan, Alexander Yu. Niktin, Zoe Hall, David Carling
Summary: Emerging evidence suggests that metabolic dysregulation is a driver of prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK), a master regulator of metabolism, has a protective effect on PCa progression in vivo. AMPK activation induces the expression of PGC1a, leading to catabolic metabolic reprogramming in PCa cells. This reprogramming inhibits PCa disease progression and is associated with the inhibition of a gene network involved in cell cycle regulation.
Article
Biology
Yanquan Li, Youwei Hu, Zhengquan Wang, Tingting Lu, Yiting Yang, Hua Diao, Xiaoguo Zheng, Chong Xie, Ping Zhang, Xuelian Zhang, Yuchuan Zhou
Summary: The IKBA signaling pathway in mature sperm regulates sperm motility and controls fatty acid beta-oxidation metabolism. Inhibition of IKBA phosphorylation significantly enhances sperm motility and increases fatty acid beta-oxidation.
COMMUNICATIONS BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Jian-shuai Yu, Tao Huang, Yu Zhang, Xin-tao Mao, Ling-jie Huang, Yi-ning Li, Ting-ting Wu, Jiang-yan Zhong, Qian Cao, Yi-yuan Li, Jin Jin
Summary: The classic NF-kappa B pathway is crucial in immune responses and inflammatory diseases. This study showed that IKK beta ubiquitination on lysine-238 increases during inflammation, with USP16 identified as a key regulator affecting p105 phosphorylation. Elevated expression of USP16 in colon macrophages of IBD patients and conditional knockout of USP16 in myeloid cells resulted in reduced severity of IBD, providing insights for targeted intervention therapy.
Article
Biochemistry & Molecular Biology
Eleonora Vecchio, Nancy Nistico, Gaetanina Golino, Enrico Iaccino, Domenico Maisano, Selena Mimmi, Annamaria Aloisio, Maurizio Renna, Angelica Avagliano, Alessandro Arcucci, Giuseppe Fiume, Ileana Quinto
Summary: The IBTK gene encodes the IBtk alpha protein, which plays a role in the regulation of MYC-dependent B-lymphomagenesis. Mechanistically, IBtk alpha indirectly activates the beta-catenin-dependent transcription of the MYC gene by modulating GSK3 beta. Silencing IBtk alpha leads to downregulation of MYC expression and increased apoptosis in Burkitt's lymphoma cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Emilia Pascale, Carmen Caiazza, Martina Paladino, Silvia Parisi, Fabiana Passaro, Massimiliano Caiazzo
Summary: Cell reprogramming is a groundbreaking technology that can generate various cell types by converting somatic cells and modulating the expression of key transcription factors. The role of microRNAs in the reprogramming processes of generating pluripotent stem cells, neurons, and cardiomyocytes is significant and has potential biomedical applications.
Article
Biochemistry & Molecular Biology
Selena Mimmi, Domenico Maisano, Vincenzo Dattilo, Massimo Gentile, Federico Chiurazzi, Alessandro D'Ambrosio, Annamaria Zimbo, Nancy Nistico, Annamaria Aloisio, Eleonora Vecchio, Giuseppe Fiume, Enrico Iaccino, Ileana Quinto
Summary: Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease with variable clinical courses among different patients. This study discovered the possible existence of multiple independent CLL clones within the same patient. By selecting a peptide binder that binds to specific clone cells using phage display libraries and performing flow cytometry, it was found that the specific clone cells expressed more genes involved in survival and apoptosis escape processes compared to other clone cells, and they did not carry characteristic genetic lesions.
Article
Biochemistry & Molecular Biology
Veronica Romano, Maria Rosaria Ruocco, Pietro Carotenuto, Anna Barbato, Alessandro Venuta, Vittoria Acampora, Sabrina De Lella, Elena Vigliar, Antonino Iaccarino, Giancarlo Troncone, Gaetano Cali, Luigi Insabato, Daniela Russo, Brunella Franco, Stefania Masone, Nunzio Velotti, Antonello Accurso, Tommaso Pellegrino, Giuseppe Fiume, Immacolata Belviso, Stefania Montagnani, Angelica Avagliano, Alessandro Arcucci
Summary: Breast cancer-associated fibroblasts (BCAFs) promote breast cancer progression by interacting with cancer cells. In an in vitro experiment, BCAFs became inactivated after 216 hours of 3D culture, resulting in a cytostatic effect on MCF-7 cells. Reverted BCAFs also exhibited an inactivated phenotype and inhibited the migration of MCF-7 cells. These findings suggest that deactivation of BCAFs without drug treatment reduces their ability to sustain breast cancer progression in vitro.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Transplantation
Patrizia Lombari, Massimo Mallardo, Oriana Petrazzuolo, Joseph Amruthraj Nagoth, Giuseppe Fiume, Roberto Scanni, Anna Iervolino, Sara Damiano, Annapaola Coppola, Margherita Borriello, Diego Ingrosso, Alessandra F. Perna, Miriam Zacchia, Francesco Trepiccione, Giovambattista Capasso
Summary: The study identified the involvement of miRNAs, including miR-23a, in the onset of salt-sensitive hypertension in the medullary thick ascending limb (mTAL) of rats. The downregulation of miR-23a in the mTAL cells led to the upregulation of NHE1, a protein involved in sodium reabsorption and blood pressure regulation. The findings suggest a potential role of miR-23a in mTAL function following high salt intake.
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Review
Oncology
Angelica Avagliano, Giuseppe Fiume, Claudio Bellevicine, Giancarlo Troncone, Alessandro Venuta, Vittoria Acampora, Sabrina De Lella, Maria Rosaria Ruocco, Stefania Masone, Nunzio Velotti, Pietro Carotenuto, Massimo Mallardo, Carmen Caiazza, Stefania Montagnani, Alessandro Arcucci
Summary: This article reviews the role of cancer-associated fibroblasts (CAFs) in thyroid cancer, highlighting the importance of studying CAFs' contribution to understanding the mechanisms of cancer growth and developing new therapeutic strategies.
Review
Oncology
Simona Laurino, Ludmila Carmen Omer, Francesco Albano, Graziella Marino, Antonella Bianculli, Angela Pia Solazzo, Alessandro Sgambato, Geppino Falco, Sabino Russi, Anna Maria Bochicchio
Summary: This study retrospectively analyzed the records of 186 sarcoma patients, among which seven were diagnosed with secondary radiation-induced sarcomas (RIS). Five of the RIS cases occurred in patients with breast cancer, and two occurred in patients with head and neck cancer. Treatment for RIS included radiation therapy, chemotherapy, and electrochemotherapy. The median survival time for RIS patients was 36 months, and no significant association was found between age, latency time, age at RIS diagnosis, and survival differences.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Carmen Caiazza, Teresa Brusco, Federica D'Alessio, Massimo D'Agostino, Angelica Avagliano, Alessandro Arcucci, Concetta Ambrosino, Giuseppe Fiume, Massimo Mallardo
Summary: This study demonstrates the important role of STING in antigen presentation. The absence of STING leads to impairment of peptide presentation and dampened immune response activation. This has significant implications for understanding the role of STING in immune mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Genetics & Heredity
Selena Mimmi, Nicola Lombardo, Domenico Maisano, Giovanna Piazzetta, Corrado Pelaia, Girolamo Pelaia, Marta Greco, Daniela Foti, Vincenzo Dattilo, Enrico Iaccino
Summary: Dupilumab has been proven effective in treating diseases such as asthma and atopic dermatitis, and now its use as add-on therapy for patients with CRSwNP could lead to reduced remission time and improved quality of life. The study also showed that miRNAs may serve as potential biomarkers for immune modulation. Preliminary data indicated that dupilumab treatment led to a reduction in inflammation and modulation of specific miRNAs related to proliferation, inflammation, and drug-resistance.
Article
Biochemistry & Molecular Biology
Teresa Peluso, Valeria Nittoli, Carla Reale, Immacolata Porreca, Filomena Russo, Luca Roberto, Antonia Giacco, Elena Silvestri, Massimo Mallardo, Mario De Felice, Concetta Ambrosino
Summary: Early life exposure to Endocrine Disruptor Chemicals (EDCs), such as the pesticide Chlorpyrifos (CPF), has been found to affect thyroid activity, glucose metabolism, and lipid metabolism. In this study, the researchers investigated the effects of CPF exposure on the metabolism and signaling of thyroid hormones (THs) and lipid/glucose metabolism in mice. They found that these processes were altered in males that were exposed to CPF, leading to hypothyroidism and systemic hyperglycemia. Additionally, the researchers discovered that CPF affected glucose metabolism and TH levels through the modulation of FOXO1 activity in liver cells. These findings highlight the importance of considering the intergenerational and sex-specific effects of CPF exposure on metabolic homeostasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Nancy Nistico, Annamaria Aloisio, Antonio Lupia, Anna Maria Zimbo, Selena Mimmi, Domenico Maisano, Rossella Russo, Fabiola Marino, Mariangela Scalise, Emanuela Chiarella, Teresa Mancuso, Giuseppe Fiume, Daniela Omodei, Antonella Zannetti, Giuliana Salvatore, Ileana Quinto, Enrico Iaccino
Summary: In this study, we used phage display to select two highly specific peptide ligands for targeting the overexpressed EGFR in TNBC cells. Molecular docking predicted the peptides' binding affinities and sites on the extracellular domain of EGFR. Flow cytometry validated the binding of FITC-conjugated peptides to TNBC cells. Confocal microscopy confirmed the peptide binding specificity to EGFR-positive tumor tissues. These peptides could be used in conjunction with nanoparticles for tumor-targeted delivery of anticancer drugs.