Review
Biochemistry & Molecular Biology
Longfei Deng, Xuan Zhai, Ping Liang, Hongjuan Cui
Summary: TRAIL holds therapeutic potential in cancer treatment, but many cancers, including GBM, exhibit resistance. Recent studies have identified new mechanisms in regulating TRAIL-induced apoptosis in GBM and effective combinatorial strategies. The TRAIL/TRAIL death receptor axis may have future clinical applications for GBM treatment.
Article
Cell Biology
Emir Bozkurt, Heiko Dussmann, Manuela Salvucci, Brenton L. Cavanagh, Sandra Van Schaeybroeck, Daniel B. Longley, Seamus J. Martin, Jochen H. M. Prehn
Summary: The study reveals that TRAIL signaling not only activates apoptosis in colon cancer cells but also induces entosis through TRAIL receptors and the structural presence of caspase-8. The association of TRAIL signaling with cell-in-cell structures is significant in colorectal cancer, especially in the context of patient prognosis. Factors controlling entosis in tumors remain to be elucidated despite the evidence of entosis in cancers.
JOURNAL OF CELL BIOLOGY
(2021)
Review
Oncology
Deepika Singh, Mallika Tewari, Sunita Singh, Gopeshwar Narayan
Summary: TRAIL is a potential anticancer therapeutic agent, but clinical trials have shown disappointing results. Recent developments in overcoming cancer cell resistance to TRAIL-induced apoptosis, such as protein modification, combination therapy and TRAIL-based gene therapy, appear promising.
Article
Medicine, General & Internal
Liu Shi, Yu Xiong, Xiaoyan Hu, Zhihao Wang, Conghua Xie
Summary: In this study, it was found that inhibition of BRD4 or genetic knock-down of BRD4 can increase the sensitivity of lung cancer cells to TRAIL, and this sensitization is not related to death receptors DR4 and DR5. The results suggest that a combination therapy with TRAIL and BRD4 inhibitors may be a promising strategy to overcome TRAIL resistance in NSCLC.
INTERNATIONAL JOURNAL OF MEDICAL SCIENCES
(2021)
Article
Oncology
Yan Wang, Qiong Lei, Cangjie Shen, Nan Wang
Summary: NCTR25-TRAIL fusion protein self-assembles into polymers with high cytotoxicity. Multivalent TRAILs specifically activate DR4 and DR5, triggering more efficient signaling pathways. NCTR25-TRAIL demonstrates better in vivo antitumor activity compared to TRAIL.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2021)
Review
Physiology
Laurel A. Grisanti
Summary: Cardiovascular disease is a leading cause of death globally. Cardiomyocyte death, which occurs in heart damage and stress, contributes to cardiac dysfunction and further damages the heart. Apoptosis, a regulated form of cell death, can occur through intrinsic or extrinsic pathways. The poorly characterized TNF-related ligand TRAIL and its receptors have been found to play a role in cardiac pathology. This article aims to provide an overview of the current understanding of TRAIL and its receptors in normal and pathological conditions in the heart.
FRONTIERS IN PHYSIOLOGY
(2023)
Article
Materials Science, Multidisciplinary
Xianzhou Huang, Haijun Li, Chunqing Ou, Yaqian Shu, Rui Luo, Xinchao Li, Shouchun Chen, Qinjie Wu, Changyang Gong, Lei Liu
Summary: The study demonstrates that a selfsustaining nanoplatform (SSN) can effectively reverse the downregulation of death receptors and remove blockage of XIAPs and survivin in TRAIL-resistant pancreatic cancer, providing a source-broadening and expenditure-reducing strategy to coactivate extrinsic and intrinsic apoptosis. This positive feedback loop not only broadens the source of death receptors but also reduces the expenditure of caspases by counteracting the inhibition of XIAPs and survivin, ultimately overcoming TRAIL-resistance in pancreatic cancer.
MATERIALS & DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Liya Qin, Jian Zou, Alexandra Barnett, Ryan P. Vetreno, Fulton T. Crews, Leon G. Coleman
Summary: The study reports the role of TLR7-mediated apoptotic neuronal death in alcohol use disorder. It suggests that TRAIL may act as a mediator of neuronal apoptosis downstream of TLR7 activation and represent a potential therapeutic target for slowing neurodegeneration in multiple diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Manjari Kundu, Yoshimi Endo Greer, Jennifer L. Dine, Stanley Lipkowitz
Summary: This review discusses the signaling components and mechanisms of the TRAIL pathway, as well as the challenges and potential solutions for TRAIL/DR targeted therapy in TNBC clinical trials. The article also explores the pharmacokinetic and pharmacodynamic properties of DR agonists, patient selection through predictive biomarkers, and potential combination therapies. Additionally, recent findings on the impact of TRAIL treatment on the immune response and novel strategies to address these challenges are discussed.
Article
Oncology
Jocelyn E. Ray, Marie D. Ralff, Aakash Jhaveri, Lanlan Zhou, David T. Dicker, Eric A. Ross, Wafik S. El-Deiry
Summary: ONC201 demonstrated promising activity in patients with advanced endometrial cancer by upregulating DR5 and sensitizing tumors to TRAIL. The combination of ONC201 and TRAIL promoted cell death in endometrial cancer models in vitro and in vivo, suggesting a novel cancer therapeutic strategy.
CANCER BIOLOGY & THERAPY
(2021)
Article
Genetics & Heredity
Atsushi Watanabe, Kunio Miyake, Koshi Akahane, Kumiko Goi, Keiko Kagami, Hideo Yagita, Takeshi Inukai
Summary: Immunotherapies specific for BCP-ALL, such as anti-CD19 CAR T-cells and blinatumomab, have significantly improved outcomes in refractory cases. The methylation status of DR4 and DR5 genes is associated with gene expression levels, cell-surface expression, and TRAIL-sensitivities, suggesting potential clinical relevance in predicting immunotherapy efficacy. Evaluating methylation status of DR4 and DR5 genes may be informative in certain cases with unfavorable karyotypes.
Article
Pharmacology & Pharmacy
Shuai Tang, Yichen Duan, Tao Yuan, Yutinh Hu, Liang Yuan, Ning Shen, Yixian Fu, Congying Pu, Xiaomin Wang, Jun Xu, Xiaojing Lan, Ying Zheng, Yu Zhou, Hong Zhu, Jian Ding, Meiyu Geng, Min Huang
Summary: This study identifies tetrandrine as a natural product that can enhance the therapeutic effect of MAPK inhibitors in KRAS-mutant PDAC. Tetrandrine stabilizes DR4/DR5 protein by impairing ubiquitination-mediated protein degradation, thereby promoting apoptosis in PDAC cells.
PHARMACOLOGICAL RESEARCH
(2023)
Article
Food Science & Technology
Chih-Chuan Teng, Shui-Yi Tung, Ko-Chao Lee, Kam-Fai Lee, Wen-Shih Huang, Chien-Heng Shen, Meng-Chiao Hsieh, Cheng-Yi Huang, Jiunn-Ming Sheen, Hsing-Chun Kuo
Summary: The study revealed that CIL-102 significantly induces apoptosis in gastric cancer cells, along with increased production of ROS and intracellular levels of Ca2+. CIL-102 induces G2/M phase arrest in gastric cancer cells through the inactivation of CDK1/cyclin B1, involving various signaling pathways.
FOOD AND CHEMICAL TOXICOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Nana Ma, Keman Cheng, Qingqing Feng, Guangna Liu, Jie Liang, Xiaotu Ma, Zhiqiang Chen, Yichao Lu, Xinwei Wang, Wei He, Hu Xu, Shan Wu, Jiajia Zou, Quanwei Shi, Guangjun Nie, Xiao Zhao
Summary: In this study, a flat rectangular DNA origami is used as a display scaffold and a strategy called engraving-printing is developed to rapidly decorate three TRAIL monomers onto its surface to form DNA-TRAIL3 trimers. By comparing the receptor affinity, agonistic activity, and cytotoxicity, it is found that the critical interligand distance of DNA-TRAIL3 trimers to induce death receptor clustering and resulting apoptosis is approximately 40 nm.
Review
Pharmacology & Pharmacy
Anne V. Yagolovich, Marine E. Gasparian, Dmitry A. Dolgikh
Summary: The TRAIL apoptotic pathway is widely studied in targeted antitumor therapy. Researchers focus on the design of novel nanodelivery systems to enhance apoptotic signaling and achieve a synergistic effect by encapsulating multiple therapeutic molecules. This review summarizes recent innovative developments in the design of nanodelivery systems modified with TRAIL pathway-targeting ligands.
Article
Chemistry, Medicinal
Liridona Useini, Marija Mojic, Markus Laube, Peter Loennecke, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Jens Pietzsch, Evamarie Hey-Hawkins
Summary: Fenoprofen is a common NSAID used to treat rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis, and gout. It inhibits the synthesis of prostaglandins by blocking both COX-1 and COX-2 isoforms. Modifications using carborane clusters showed stronger antitumor potential compared to aryl-based compounds.
Article
Immunology
Qing Li, Jialuo He, Senlin Li, Cheng Tian, Jian Yang, Huimin Yuan, Yi Lu, Paolo Fagone, Ferdinando Nicoletti, Ming Xiang
Summary: Pancreatic cancer (PC) has a cold tumor immune microenvironment (TIME) with minimal dendritic cell (DC) and T cell infiltration, leading to inadequate immunotherapy and chemotherapy. Combining gemcitabine (GEM) with ginsenoside Rh2 (Rh2) can enhance tumor immunogenicity and induce lasting anti-tumor immunity in PC. The activation of DCs by Rh2 via the CARD9-BCL10-MALT1/NF-KB pathway may reverse the cold TIME and optimize GEM chemotherapy, providing a potentially feasible and safe treatment strategy for PC.
CLINICAL IMMUNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Simona Aleksandrova, Ralitza Alexova, Stela Dragomanova, Reni Kalfin, Ferdinando Nicoletti, Paolo Fagone, Maria Cristina Petralia, Katia Mangano, Lyubka Tancheva
Summary: Pomegranate is a polyphenol-rich food and medicinal plant that contains various beneficial compounds. Studies have shown that these compounds can target brain cells and support their functions by regulating redox balance, proliferation, and survival. The neuroprotective effects of pomegranate are mediated by its antioxidant and anti-inflammatory properties, ability to activate signaling pathways, and regulation of mitochondrial damage. In vitro and in vivo studies have demonstrated that pomegranate polyphenols can directly affect neuronal and glial cells, as well as influence blood-brain barrier function and increase blood flow to the brain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Thomas Hach, Kasra Shakeri-Nejad, Marc Bigaud, Frank Dahlke, Massimiliano de Micco, Olivier Petricoul, Gordon Graham, Daniela Piani-Meier, Renato Turrini, Volker Brinkmann, Ferdinando Nicoletti
Summary: Maladjusted immune responses to COVID-19 can lead to immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate and its receptors play a crucial role in maintaining endothelial cell chemotaxis and barrier integrity. S1PR modulators can attenuate cytokine release and enhance the pulmonary endothelial barrier. Certain drugs used in multiple sclerosis have shown effectiveness and potential in COVID-19 patients.
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
(2023)
Article
Neurosciences
Nicole Piera Palomba, Giorgio Fortunato, Giuseppe Pepe, Nicola Modugno, Sara Pietracupa, Immacolata Damiano, Giada Mascio, Federica Carrillo, Luca Giovanni Di Giovannantonio, Laura Ianiro, Katiuscia Martinello, Viola Volpato, Vincenzo Desiato, Riccardo Acri, Marianna Storto, Ferdinando Nicoletti, Caleb Webber, Antonio Simeone, Sergio Fucile, Vittorio Maglione, Teresa Esposito
Summary: This study focuses on the common and rare variants identified in the lysosomal K+ channel TMEM175 and their association with Parkinson's disease. Through clinical and genetic analysis, the study identified several common variants and 13 highly penetrant detrimental mutations in the TMEM175 gene. Functional analysis revealed a loss of K+ conductance and impaired autophagic/lysosomal proteolytic flux in patient-derived cells, suggesting a potential role of TMEM175 gene mutations in the pathophysiology of PD.
MOLECULAR NEUROBIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Milica Markelic, Marija Mojic, Dijana Bovan, Sanja Jelaca, Zorana Jovic, Milica Puric, Djuro Koruga, Sanja Mijatovic, Danijela Maksimovic-Ivanic
Summary: Our study demonstrated that treatment of melanoma cells with hyperpolarized light (HPL) and hyper-harmonized hydroxylated fullerene water complex (3HFWC) reduced cell viability and induced senescence and reprogramming towards normal phenotype. We investigated whether these effects persisted in vivo in a mouse melanoma model with combined treatment of HPL irradiation and 3HFWC. The results showed potent antitumor effects, including growth arrest, senescent phenotype, melanocytic differentiation, and activation of antitumor immune response.
Article
Pharmacology & Pharmacy
Philipp Stockmann, Lydia Kuhnert, Wencke Leinung, Cathleen Lakoma, Birte Scholz, Svetlana Paskas, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Walther Honscha, Evamarie Hey-Hawkins
Summary: The overexpression of ATP-binding cassette (ABC) transporter proteins, particularly ABCG2, in cancer cells is a major cause of multidrug resistance (MDR) and the failure of chemotherapeutic treatments. Inhibition of ABCG2 activity during chemotherapy has the potential to reverse MDR and improve the efficacy of anti-cancer agents. However, the development of selective and non-toxic inhibitors of ABCG2 has been challenging, with limited success in clinical applications. This study focuses on the synthesis and evaluation of carboranyl quinazoline-based inhibitors of ABCG2, identifying a promising compound, DMQCd, which exhibits strong inhibitory effects and the ability to reverse MDR mediated by BCRP.
Article
Pharmacology & Pharmacy
Sebastian Braun, Svetlana Paskas, Markus Laube, Sven George, Bettina Hofmann, Peter Loennecke, Dieter Steinhilber, Jens Pietzsch, Sanja S. Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
Summary: In this study, carborane-containing dual COX-2/5-LO inhibitors were designed by incorporating metabolically stable, sterically demanding, and hydrophobic carboranes into existing inhibitors. Five carborane-containing derivatives showed high inhibitory activities towards COX-2 and 5-LO, with meta-carborane derivative 3 demonstrating higher anticancer activity compared to RWJ-63556. The accumulation of lipid droplets in cells indicated the blockage of COX-2 and 5-LO pathways, suggesting a promising approach for the design of potent dual COX-2/5-LO inhibitors.
ADVANCED THERAPEUTICS
(2023)
Article
Chemistry, Medicinal
Sebastian Braun, Svetlana Paskas, Markus Laube, Sven George, Bettina Hofmann, Peter Loennecke, Dieter Steinhilber, Jens Pietzsch, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
Summary: The presence of inflammatory mediators in the tumor microenvironment indicates cancer-related inflammatory processes, and targeting these mediators and related signal pathways may provide a rational strategy for cancer treatment. This study focuses on incorporating carboranes into dual COX-2/5-LO inhibitors, key enzymes in eicosanoid biosynthesis. The results show that carborane-based tebufelone analogs exhibit no COX inhibition but 5-LO inhibitory activity, and structural modifications enhance their anticancer activity. Thus, this strategy is promising for designing potent 5-LO inhibitors with potential application as cytostatic agents.
Review
Biochemistry & Molecular Biology
Ralitza Alexova, Simona Alexandrova, Stela Dragomanova, Reni Kalfin, Ayten Solak, Sidharth Mehan, Maria Cristina Petralia, Paolo Fagone, Katia Mangano, Ferdinando Nicoletti, Lyubka Tancheva
Summary: Pomegranate is a rich source of polyphenols that have anti-inflammatory and antioxidant activity, and can support the immune system during viral infection and recovery. Studies have shown that pomegranate polyphenol extract and its components can control immune cell infiltration, regulate cytokine secretion, inhibit viruses like SARS-CoV-2, and modulate the NF-κB pathway. Further research is needed to understand the interactions between polyphenols, viruses, and the host immune response.
Article
Biochemistry & Molecular Biology
Sebastian Braun, Sanja Jelaca, Markus Laube, Sven George, Bettina Hofmann, Peter Loennecke, Dieter Steinhilber, Jens Pietzsch, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
Summary: Targeting inflammatory mediators and related pathways is a rational strategy for cancer treatment. Incorporating carboranes into dual COX-2/5-LO inhibitors shows promise, with compounds exhibiting high 5-LO inhibitory activities. However, carborane analogs demonstrate lower anticancer activity compared to related compounds in cell viability studies. R-830-Cb, a carborane-based analog, shows potential for further mechanistic and in vivo studies due to the advantages of boron cluster incorporation.
Article
Pharmacology & Pharmacy
Aleksandr Kazimir, Benedikt Schwarze, Peter Loennecke, Sanja Jelaca, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
Summary: A new complex with potential anti-cancer properties was studied in this research. The complex showed high selectivity towards triple-negative breast cancer cells and no significant effect on other cells. This finding may provide new insights for the treatment of breast cancer.
Correction
Pharmacology & Pharmacy
Aleksandr Kazimir, Benedikt Schwarze, Peter Loennecke, Sanja Jelaca, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Evamarie Hey-Hawkins
Article
Neurosciences
Ferdinando Nicoletti, Luisa Di Menna, Luisa Iacovelli, Rosamaria Orlando, Anna Rita Zuena, P. Jeffrey Conn, Shalini Dogra, Max E. Joffe
Summary: Cellular responses to metabotropic glutamate (mGlu) receptor activation are influenced by mechanisms of receptor-receptor interaction, including receptor dimerization and complex formation with other GPCRs. The interactions between different mGlu receptor subtypes and other receptors have been studied in various brain regions and have been implicated in the pathophysiology of several neurological and psychiatric disorders. Understanding these interactions could lead to the development of new therapeutic targets for these conditions.
Article
Neurosciences
Luisa Di Menna, Rosamaria Orlando, Giovanna 'Errico, Roxana Paula Ginerete, Agata Machaczka, Carmela Maria Bonaccorso, Andrea Arena, Michela Spatuzza, Roberta Celli, Marika Alborghetti, Eleonora Ciocca, Anna Rita Zuena, Mariarosaria Scioli, Valeria Bruno, Giuseppe Battaglia, Ferdinando Nicoletti, Maria Vincenza Catania
Summary: The involvement of mGlu5 receptors in monogenic autism has been supported by various studies, but there is a lack of research on the canonical signal transduction pathway activated by these receptors in mouse models of autism. In this study, we developed a method to assess PI hydrolysis in vivo and found that mGlu5 receptor-mediated PI hydrolysis was impaired in different brain regions of mice modeling Angelman syndrome and fragile-X syndrome. These findings provide the first evidence that the canonical transduction pathway of mGlu5 receptors is downregulated in mouse models of monogenic autism.
