Article
Genetics & Heredity
Sameer H. Patel, Magdalena Bachmann, Stephanie Kadow, Gregory C. Wilson, Mostafa M. L. Abdel-Salam, Kui Xu, Simone Keitsch, Matthias Soddemann, Barbara Wilker, Katrin Anne Becker, Alexander Carpinteiro, Syed A. Ahmad, Ildiko Szabo, Erich Gulbins
Summary: The combination of the sphingosine analog FTY-720 and the mitochondrial Kv1.3 inhibitor PAPTP can induce death of pancreatic cancer cells by inhibiting acid sphingomyelinase and disrupting mitochondrial and lysosomal functions. This study reveals a previously unknown crosstalk between lysosomes and mitochondria mediated by sphingolipid metabolism.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2023)
Article
Pharmacology & Pharmacy
Kholoud K. Arafa, Hugh D. C. Smyth, Ibrahim M. El-Sherbiny
Summary: This study aimed to develop a sequential targeted core-shell nanoparticulate system for the treatment of breast cancer, utilizing the acidic extracellular environment, hypoxic tumor core, and overexpression of tumor-specific surface antigens. The core-shell NPs showed high drug encapsulation efficiency and loading capacity, successfully inducing apoptosis and cell-cycle abrogation in vitro, and demonstrating efficient anticancer activity in Solid Ehrlich carcinoma-bearing mice. In conclusion, the developed NPs proved to be effective in sequentially targeting DOX to breast cancer.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Review
Biochemistry & Molecular Biology
Nadine Abdel Hadi, Gabriela Reyes-Castellanos, Alice Carrier
Summary: Cell metabolism in cancer cells is reprogrammed to meet their high energy and biosynthetic demands, leading to alterations in redox metabolism and accumulation of reactive oxygen species (ROS). Cancer cells adapt to high ROS levels, contributing to tumorigenesis, metastasis, therapy resistance, and relapse. Combining strategies to increase ROS production and inhibit antioxidant capacity is a promising approach for pancreatic cancer therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Gilles Rademaker, Yasmine Boumahd, Raphael Peiffer, Sandy Anania, Tom Wissocq, Maude Liegeois, Geraldine Luis, Nor Eddine Sounni, Ferman Agirman, Naima Maloujahmoum, Pascal De Tullio, Marc Thiry, Akeila Bellahcene, Vincent Castronovo, Olivier Peulen
Summary: The pharmacological compound WJ460, targeting myoferlin, triggers mitophagy and ROS accumulation, leading to lipid peroxidation and apoptosis-independent cell death. Inhibitors of mitophagy and iron chelators can suppress myoferlin-induced ROS production and restore cell growth. Additionally, a synergic effect exists between ferroptosis inducers and WJ460.
Article
Polymer Science
Bing Lu, Yuying Huang, Hui Quan, Jiacheng Xia, Jin Wang, Yue Ding, Yang Wang, Yong Yao
Summary: This study developed a mitochondria-targeting multimodal phototheranostics system with excellent FLI capability and few components. The system utilized the combination of amphiphilic pillararene and a fused-ring photosensitizer to achieve a nanocarrier with outstanding mitochondria targeting and water solubility. The multifunctional nanoparticles showed good mitochondria-targeting and phototherapy effects in tumor cells.
Review
Pharmacology & Pharmacy
Delphine Quatannens, Yannick Verhoeven, Peter Van Dam, Filip Lardon, Hans Prenen, Geert Roeyen, Marc Peeters, Evelien L. J. Smits, Jonas Van Audenaerde
Summary: PDAC is a leading cause of cancer related death, with urgent need for effective therapies. Aberrant activation of the Hh signaling pathway in PDAC prompts it as a possible target for treatment, despite ongoing debate on its clinical benefits.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Pharmacology & Pharmacy
Alexander G. Raufi, Nicholas R. Liguori, Lindsey Carlsen, Cassandra Parker, Liz Hernandez Borrero, Shengliang Zhang, Xiaobing Tian, Anna Louie, Lanlan Zhou, Attila A. Seyhan, Wafik S. El-Deiry
Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with slow progress towards effective therapy, indicating an urgent need for novel treatment approaches, with autophagy potentially being a promising therapeutic target.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Utpreksha Vaish, Tejeshwar Jain, Abhi C. Are, Vikas Dudeja
Summary: PDAC is a major cause of cancer-related mortality in the western world, with CAFs playing a key role in the tumor microenvironment and being potential targets for therapy. However, there is significant heterogeneity in CAFs within PDAC, highlighting the importance of understanding and delineating this heterogeneity before targeting them for treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Hsin-Han Yang, Jen-Wei Liu, Jui-Hao Lee, Horng-Jyh Harn, Tzyy-Wen Chiou
Summary: This article reviews the regulation of RTKs/TGF beta R between PDAC and CAFs, as well as the RTKs/TGF beta R inhibitor-based clinical trials on pancreatic cancer. It discusses the importance of considering the signaling of receptor tyrosine kinases and TGF beta receptors in overcoming the obstruction in the tumor microenvironment. The impact of receptor activation on cell cycle regulation, signal transduction pathways, and apoptotic sensitivity of tumor cells is also highlighted.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Kohei Tsuji, Yuki Kida, Nobuko Koshikawa, Seigi Yamamoto, Yoshinao Shinozaki, Takayoshi Watanabe, Jason Lin, Hiroki Nagase, Keizo Takenaga
Summary: The anticancer therapy with PIP-TPPs targeting mtDNA mutations has the potential to induce cell death, even in apoptosis-resistant cancer cells, when combined with senolytics.
Article
Pharmacology & Pharmacy
Yan Ou, Ruoxiang Wang, Gina Chia-Yi Chu, Omer Hany Miligy Elmadbouh, Adrian Lim, Leland Wei-Kuo Chung, Mouad Edderkaoui, Yi Zhang, Stephen Jacob Pandol
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a disease with no effective therapeutics. A novel targeted therapy drug consisting of a tumor-targeting ligand, near-infrared (NIR) organic heptamethine carbocyanine dye (DZ), and HMG-CoA inhibitor simvastatin (SIM), is developed and its efficacy in PDAC is assessed. The drug significantly inhibits tumor growth, re-sensitizes therapeutically resistant PDAC cells to conventional therapies, and kills cancer cells through unique pathways involving decreasing mitochondrial bioenergetics and increasing ROS production.
ADVANCED THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Tadataka Takagi, Rina Fujiwara-Tani, Shiori Mori, Shingo Kishi, Yukiko Nishiguchi, Takamitsu Sasaki, Ruiko Ogata, Ayaka Ikemoto, Rika Sasaki, Hitoshi Ohmori, Yi Luo, Ujjal Kumar Bhawal, Masayuki Sho, Hiroki Kuniyasu
Summary: Gemcitabine resistance in pancreatic ductal adenocarcinoma cells is associated with decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness caused by mitochondrial damage. Hypoxia may promote this process. Treatment with lauric acid restores gemcitabine sensitivity by activating oxidative phosphorylation. Further clinical validation of lauric acid in gemcitabine resistance is needed in the future.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Zoe X. Malchiodi, Louis M. Weiner
Summary: This article discusses the interaction between natural killer (NK) cells and cancer-associated fibroblasts (CAFs) in pancreatic cancer, highlighting the importance of developing novel targeted therapies. Understanding and targeting this interplay may hold potential for improving immune response and survival in patients with pancreatic cancer.
Article
Oncology
Nicolas A. Fraunhoffer, Daniel Closa, Emma Folch-Puy, Analia Meilerman Abuelafia, Ezequiel Luis Calvo, Eduardo Chuluyan, Juan Iovanna
Summary: The study demonstrates that REG3 beta plays a role in promoting PDAC progression by over-activating CTGF, making it a promising therapeutic target. The far microenvironment, producing active secretory factors, is essential for PDAC progression and some of these factors could be utilized as therapeutic targets.
Article
Chemistry, Multidisciplinary
Hannah K. Gruenwald, Robert J. Kerns
Summary: Triphenylphosphonium (TPP+) conjugates are effective in targeting drugs and probes to the mitochondria due to their lipophilic character and large cationic radius. Different para-substitutions on the phenyl rings of xTPP+ conjugates have varying levels of dose-mediated cytotoxicity due to differing potencies of uncoupling. The stability of a CF3-TPP+ conjugate in aqueous DMSO can be improved by the presence of the metal chelator DTPA, which forms a noncovalent protective complex with TPP+ moieties.
Article
Psychiatry
Maurizio Fava, Stephen Stahl, Luca Pani, Sara De Martin, Marco Pappagallo, Clotilde Guidetti, Andrea Alimonti, Ezio Bettini, Richard M. Mangano, Thomas Wessel, Marc de Somer, Judy Caron, Ottavio V. Vitolo, Gina R. DiGuglielmo, Adam Gilbert, Hiren Mehta, Morgan Kearney, Andrea Mattarei, Marco Gentilucci, Franco Folli, Sergio Traversa, Charles E. Inturrisi, Paolo L. Manfredi
Summary: The study examined the effects of REL-1017 in patients with inadequate responses to antidepressant treatments. The results showed that REL-1017 had positive effects on improving depressive symptoms and had favorable safety profiles.
AMERICAN JOURNAL OF PSYCHIATRY
(2022)
Article
Oncology
Weiwei Li, Gregory C. Wilson, Magdalena Bachmann, Jiang Wang, Andrea Mattarei, Cristina Paradisi, Michael J. Edwards, Ildiko Szabo, Erich Gulbins, Syed A. Ahmad, Sameer H. Patel
Summary: The study evaluated the expression of Kv1.3 potassium channel in pancreatic ductal adenocarcinoma (PDAC) and found that it could be a novel therapeutic target for PDAC treatment. The use of Kv1.3 inhibitors in combination with cytotoxic chemotherapies showed significant reduction in tumor growth.
Letter
Pharmacology & Pharmacy
Clotilde Guidetti, Giulia Serra, Luca Pani, Marco Pappagallo, Gino Maglio, Monia Trasolini, Sara De Martin, Andrea Mattarei, Francesco Bifari, Franco Folli, Paolo L. Manfredi, Maurizio Fava
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Ezio Bettini, Sara De Martin, Andrea Mattarei, Marco Pappagallo, Stephen M. Stahl, Francesco Bifari, Charles E. Inturrisi, Franco Folli, Sergio Traversa, Paolo L. Manfredi
Summary: REL-1017 is a promising candidate for rapid antidepressant treatment as it acts as a novel antagonist for N-methyl-D-aspartate receptors (NMDARs). This study demonstrates that REL-1017 can reduce the influx of calcium ions induced by L-glutamate, quinolinic acid, and gentamicin in various cell lines expressing different NMDAR subtypes.
Article
Chemistry, Medicinal
Ezio Bettini, Stephen M. Stahl, Sara De Martin, Andrea Mattarei, Jacopo Sgrignani, Corrado Carignani, Selena Nola, Patrizia Locatelli, Marco Pappagallo, Charles E. Inturrisi, Francesco Bifari, Andrea Cavalli, Andrea Alimonti, Luca Pani, Maurizio Fava, Sergio Traversa, Franco Folli, Paolo L. Manfredi
Summary: Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders, and uncompetitive NMDAR channel blockers are emerging drugs for the treatment of major depressive disorder (MDD) and other neuropsychiatric diseases.
Article
Cell Biology
Silvia Muccioli, Roberto Ciaccio, Valentina Brillo, Luigi Leanza
Summary: Tissue Transglutaminases (TGs) are crosslinking enzymes that play a role in the development and progression of cancers by remodeling the tumor microenvironment. This study investigated the distribution and prognostic significance of TGs in cancer patients using publicly available datasets. The results showed that skin cutaneous melanoma (SKCM) had the highest abundance of TGs mutations. Among all TGs, TG2 was the only member whose expression was associated with better overall survival in SKCM, despite its increased expression with worsening tumor phenotype. The analysis revealed a positive association between TG2 expression and anti-tumoral immune response, suggesting TG2 as a promising immune biomarker for prognosis in SKCM.
CELL DEATH DISCOVERY
(2022)
Article
Biochemistry & Molecular Biology
Stephen M. Stahl, Sara De Martin, Andrea Mattarei, Ezio Bettini, Luca Pani, Clotilde Guidetti, Franco Folli, Marc de Somer, Sergio Traversa, Charles E. Inturrisi, Marco Pappagallo, Marco Gentilucci, Andrea Alimonti, Maurizio Fava, Paolo L. Manfredi
Summary: This article presents a hypothesis on the mechanism of action for the rapid antidepressant effects of esmethadone and other NMDAR antagonists, and proposes a corresponding disease mechanism for major depressive disorder (MDD). Through regulating the Ca2+ currents of GluN2D subtypes, physiological neural plasticity can be restored, thereby improving depressive-like behavior and MDD in patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Medicine, Research & Experimental
Sofia Parrasia, Ildiko Szabo, Mario Zoratti, Lucia Biasutto
Summary: Central nervous system diseases are difficult to treat due to the blood-brain barrier (BBB), which prevents most drugs from reaching the brain. Peptides show promise in helping drugs cross the BBB and target the brain. However, there are challenges such as potential toxic effects, short in vivo lifespan, and inadequate drug levels in the brain.
MOLECULAR PHARMACEUTICS
(2022)
Article
Cell Biology
Magdalena Bachmann, Andrea Rossa, Tatiana Varanita, Bernard Fioretti, Lucia Biasutto, Stefan Milenkovic, Vanessa Checchetto, Roberta Peruzzo, Syed A. Ahmad, Sameer H. Patel, Robert Lukowski, Michael J. Edwards, Matteo Ceccarelli, Erich Gulbins, Mario Zoratti, Andrea Mattarei, Ildiko Szabo
Summary: This study reports the synthesis and characterization of two mitochondria-targeted TRAM-34 derivatives, which induce cancer cell death and reduce cancer cell migration, showing potential against tumor growth and metastasis.
CELL DEATH & DISEASE
(2022)
Article
Multidisciplinary Sciences
Caterina Marchioretti, Giulia Zanetti, Marco Pirazzini, Gaia Gherardi, Leonardo Nogara, Roberta Andreotti, Paolo Martini, Lorenzo Marcucci, Marta Canato, Samir R. Nath, Emanuela Zuccaro, Mathilde Chivet, Cristina Mammucari, Marco Pacifici, Anna Raffaello, Rosario Rizzuto, Andrea Mattarei, Maria A. Desbats, Leonardo Salviati, Aram Megighian, Gianni Soraru, Elena Pegoraro, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Chiara Romualdi, Andrew P. Lieberman, Gopal J. Babu, Marco Sandri, Bert Blaauw, Manuela Basso, Maria Pennuto
Summary: Marchioretti and colleagues demonstrate that there are reversible alterations in gene expression related to muscle contraction and mitochondrial respiration in the skeletal muscle of SBMA mice and patients. These alterations are accompanied by calcium accumulation inside the mitochondria, motor dysfunction, and late changes in muscle structure. The deregulation of expression of genes involved in excitation-contraction coupling (ECC) occurs with sexual maturity and androgen increase in the serum. Surgical castration and AR silencing alleviate the early and late pathological processes, indicating an androgen-dependent nature of these alterations.
NATURE COMMUNICATIONS
(2023)
Review
Clinical Neurology
Maurizio Fava, Stephen M. M. Stahl, Sara De Martin, Andrea Mattarei, Ezio Bettini, Stefano Comai, Andrea Alimonti, Francesco Bifari, Luca Pani, Franco Folli, Clotilde Guidetti, Alberto Furlan, Jacopo Sgrignani, Patrizia Locatelli, Andrea Cavalli, Cedric O'Gorman, Sergio Traversa, Charles E. E. Inturrisi, Marco Pappagallo, Paolo L. L. Manfredi
Summary: This review article discusses recent studies on the development of esmethadone as a potential new drug. Esmethadone is a member of the pharmacological class of uncompetitive NMDAR antagonists and has shown efficacy for MDD and other diseases. The article also compares esmethadone with other NMDAR antagonists. It presents data from in silico, in vitro, in vivo, and clinical studies that contribute to our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants has implications for the neurobiology of MDD and other neuropsychiatric disorders.
EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE
(2023)
Article
Pharmacology & Pharmacy
Sofia Parrasia, Andrea Rossa, Nicola Roncaglia, Andrea Mattarei, Claudia Honisch, Ildiko Szabo, Paolo Ruzza, Lucia Biasutto
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a common and aggressive type of pancreatic cancer. Peptides, such as A7R, that can target specific proteins expressed on cancer cells, show promise in PDAC therapy. In this study, A7R-drug conjugates were tested as a potential PDAC-targeting strategy using PAPTP as a cargo.
Article
Biochemistry & Molecular Biology
Beatrice Angi, Silvia Muccioli, Ildiko Szabo, Luigi Leanza
Summary: Potassium channels are highly expressed in cancer cells and play a role in cell proliferation by modulating various cellular processes. This study investigated the correlation between Kv channel expression and survival rate in five different types of cancer. The analysis revealed a prognostic role of specific Kv channel genes in certain cancer types, and differences in gene expression and immune cell infiltration may contribute to the observed differences in prognosis. Overall, the study highlights the promising correlation between Kv channel expression and survival rate in cancer.
Article
Cell Biology
Doni Davide, Cavion Federica, Bortolus Marco, Baschiera Elisa, Muccioli Silvia, Tombesi Giulia, d'Ettorre Federica, Daniele Ottaviani, Marchesan Elena, Leanza Luigi, Greggio Elisa, Ziviani Elena, Russo Antonella, Bellin Milena, Sartori Geppo, Carbonera Donatella, Salviati Leonardo, Costantini Paola
Summary: Friedreich ataxia (FRDA) is a rare neurodegenerative disease caused by an expanded GAA repeat in the FXN gene, leading to reduced expression of frataxin. This study explores the interaction between frataxin and respiratory complexes I, II and III, and finds that the decreased level of frataxin specifically affects the FeS cluster content of complex I in FRDA patients' cells. Additionally, a frataxin-like protein from a different organism is found to improve the mitochondrial respiratory phenotype in FRDA patients' cells.
CELL DEATH & DISEASE
(2023)