Article
Nutrition & Dietetics
Kouji Fukuyama, Eishi Motomura, Motohiro Okada
Summary: Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but have different effects on weight gain and metabolic complications. The underlying reasons for these differences are still unknown.
Review
Psychology, Developmental
Wisam Al Jumaili, Ashraf Muzwagi, Kaushal Shah, Chintan Trivedi, Priya Durga, Zeeshan Mansuri, Shailesh Jain, Yousif Al Jumaili
Summary: This study systematically reviewed and summarized existing clinical studies evaluating the pharmacological intervention for atypical antipsychotic induced weight gain in the pediatric population. The study found that metformin is the most studied medication and can significantly reduce body weight and BMI with mild side effects. Other adjunct medications have varying effects and side effects. Lifestyle modification and adding adjuvant medication are potential strategies to mitigate the negative metabolic effects of antipsychotics. Metformin has the strongest evidence, but further clinical studies are needed for other options.
CHILD PSYCHIATRY & HUMAN DEVELOPMENT
(2022)
Review
Psychology, Multidisciplinary
Yanisa Wannasuphoprasit, Stig Ejdrup Andersen, Maria J. Arranz, Rosa Catalan, Gesche Jurgens, Sanne Maartje Kloosterboer, Henrik Berg Rasmussen, Anjali Bhat, Haritz Irizar, Dora Koller, Renato Polimanti, Baihan Wang, Eirini Zartaloudi, Isabelle Austin-Zimmerman, Elvira Bramon
Summary: The CYP2D6 genetic variation may influence weight gain in individuals taking antipsychotic medications, but further large-scale studies are needed to confirm the association.
FRONTIERS IN PSYCHOLOGY
(2022)
Article
Multidisciplinary Sciences
Maarten Bak, Marjan Drukker, Shauna Cortenraad, Emma Vandenberk, Sinan Guloksuz
Summary: This meta-analysis found that antipsychotics are associated with body weight gain, regardless of psychiatric diagnosis.
Article
Pharmacology & Pharmacy
Farhana Islam, Xiaoyu Men, Kazunari Yoshida, Clement C. Zai, Daniel J. Mueller
Summary: Pharmacogenetics research has shown that genetic factors influence the efficacy and tolerability of antipsychotic treatment, with the most robust findings related to associations between polymorphisms in CYP2D6 and exposure and response to specific antipsychotics. Product labels and guidelines have provided dosing recommendations based on CYP2D6 metabolizer phenotypes.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Health Care Sciences & Services
Gesche Jurgens, Benjamin Skov Kaas-Hansen, Merete Nordentoft, Thomas Werge, Stig Ejdrup Andersen
Summary: This study found an association between genetically predicted CYP2D6 metabolic capacity and antipsychotic-induced weight gain. The results showed significant weight gain in both CYP2D6 poor metabolizers and ultrarapid metabolizers after taking antipsychotic drugs.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Psychology, Clinical
Maryrose Bauschka, Ashlie Watters, Dan Blalock, Asma Farooq, Philip Mehler, Dennis Gibson
Summary: There are currently no FDA-approved medications for the treatment of anorexia nervosa (AN). While the use of antipsychotic medications for AN patients has produced conflicting results, some individuals might benefit from their use. However, the fear of weight gain associated with antipsychotic medications can limit their willingness to try these drugs. This study found that the use of atypical antipsychotics did not affect the rate of weight gain in individuals with extreme AN.
JOURNAL OF EATING DISORDERS
(2023)
Article
Cell Biology
Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue-Nan Sun, Zhuzhen Zhang, Jan-Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C. Wyler, May-Yun Wang, Juli Bai, Xianlin Han, Christine M. Kusminski, Ningyan Zhang, Zhiqiang An, Joel K. Elmquist, Olivia Osborn, Chen Liu, Philipp E. Scherer
Summary: Antipsychotic drugs can cause weight gain and diabetes, and hyperleptinemia plays a key role. Suppression of leptin rise can reduce the adverse effects of these drugs.
SCIENCE TRANSLATIONAL MEDICINE
(2023)
Article
Psychiatry
Luisa M. Burin, Margaret K. Hahn, Neusa S. da Rocha, Therese van Amelsvoort, Agna A. Bartels-Velthuis, Richard Bruggeman, Lieuwe de Haan, Frederike Schirmbeck, Claudia J. P. Simons, Jim van Os, Wiepke Cahn
Summary: Patients undergoing long-term treatment with antipsychotics or antipsychotics combined with other psychotropics experience significant weight gain, especially those taking clozapine, olanzapine, or quetiapine.
PSYCHIATRY RESEARCH
(2022)
Article
Psychology, Developmental
Hua Chen, Ning Lyu, Wenyaw Chan, Austin De La Cruz, Chadi Calarge
Summary: This study examines the utilization and predictors of adjuvant metformin among pediatric recipients of second-generation antipsychotics. The findings suggest that the utilization of adjuvant metformin is uncommon among pediatric SGA recipients, and early introduction of the medication among nonobese children is rare.
JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY
(2023)
Review
Endocrinology & Metabolism
Helene Speyer, Casper Westergaard, Nikolai Albert, Mette Karlsen, Anne Emilie Sturup, Merete Nordentoft, Jesper Krogh
Summary: The study found that reducing dosage, discontinuing medication, or switching to a partial agonist can lead to a small but significant weight loss of around 1.5 kg. The overall weight change from pre to post intervention was a reduction of 1.13 kg.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Review
Psychiatry
Kenn Lee, Seri Abraham, Robert Cleaver
Summary: This study evaluated the efficacy of licensed weight loss medications (WLMs) for treating antipsychotic-induced weight gain (AIWG) and obesity in schizophrenia and psychosis. The findings showed that liraglutide had the strongest evidence compared to other licensed WLMs in improving weight, BMI, waist circumference, HbA1c, cholesterol, and LDL readings. This evidence supports the use of liraglutide in treating AIWG and OSP.
GENERAL HOSPITAL PSYCHIATRY
(2022)
Article
Clinical Neurology
Javier Vazquez-Bourgon, Jaqueline Mayoral-van Son, Marcos Gomez-Revuelta, Maria Juncal-Ruiz, Victor Ortiz-Garcia de la Foz, Diana Tordesillas-Gutierrez, Rosa Ayesa-Arriola, Miquel Bioque, Benedicto Crespo-Facorro
Summary: Discontinuing antipsychotic treatment in patients with first episode psychosis resulted in lower weight gain and better metabolic parameters at the 10-year follow-up, although the effects were not sufficient for complete reversal to normal levels.
INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY
(2021)
Review
Medicine, Research & Experimental
Octavian Vasiliu
Summary: Patients with psychiatric disorders undergoing antipsychotic treatment, especially with atypical agents, are more prone to metabolic disorders (MDs) such as obesity, dyslipidemia, and type 2 diabetes. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) have shown efficacy in managing antipsychotic-induced MDs, particularly liraglutide and exenatide. However, further research is needed to evaluate the long-term effects and other metabolic variables in this specific population.
EXPERIMENTAL AND THERAPEUTIC MEDICINE
(2023)
Article
Environmental Sciences
Andrea L. Deierlein, Haotian Wu, Allan C. Just, Allison J. Kupsco, Joseph M. Braun, Emily Oken, Diana C. Soria-Contreras, Alejandra Cantoral, Ma Luisa Pizano, Nia McRae, Martha M. Tellez-Rojo, Robert O. Wright, Andrea A. Baccarelli
Summary: The study found that prenatal exposure to phthalates was negatively associated with gestational weight gain and positively associated with long-term changes in maternal weight. Further investigation is needed to understand how phthalates influence body composition and whether they contribute to the development of obesity and other cardiometabolic diseases in women.
ENVIRONMENTAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Mariasole Perrone, Simone Patergnani, Tommaso Di Mambro, Laura Palumbo, Mariusz R. Wieckowski, Carlotta Giorgi, Paolo Pinton
Summary: Maintenance of mitochondrial quality is crucial for cellular homeostasis. Mitophagy, the selective elimination of dysfunctional mitochondria, plays a significant role in various diseases, including carcinogenesis, neurodegenerative disorders, and cardiovascular pathologies. The relationship between calcium homeostasis and mitophagy is still a topic of debate.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Cell Biology
Simone Patergnani, Antonino Giattino, Nicoletta Bianchi, Carlotta Giorgi, Paolo Pinton, Gianluca Aguiari
Summary: This study reveals that inhibition of mTOR activates autophagy in ADPKD cells, leading to drug degradation through autophagic vesicles and reduced therapeutic efficacy. The combination of mTOR inhibitor and autophagy inhibitor enhances the decrease in cell proliferation caused by mTOR inhibition. Targeting MDM2, a downstream effector of mTOR signaling, prevents TP53 degradation and induces cell apoptosis, providing a new therapeutic option for ADPKD treatment.
BIOLOGY OF THE CELL
(2023)
Review
Biochemistry & Molecular Biology
Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A. Aaronson, John M. Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S. Alnemri, Lucia Altucci, Ivano Amelio, David W. Andrews, Rami Aqeilan, Eli Arama, Eric H. Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A. Barlev, Jiri Bartek, Nicolas G. Bazan, Christoph Becker, Francesca Bernassola, Mathieu J. M. Bertrand, Marco E. Bianchi, Mikhail V. Blagosklonny, J. Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D. Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A. Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H. Chen, Emily H. Cheng, Jerry E. Chipuk, John A. Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R. Cubillos-Ruiz, Peter E. Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M. Dawson, Valina L. Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J. Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J. Dixon, Brian D. Dynlacht, Wafik S. El-Deiry, John W. Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J. Garcia-Saez, Abhishek D. Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R. Green, Lloyd A. Greene, Hinrich Gronemeyer, Georg Haecker, Gyorgy Hajnoczky, J. Marie Hardwick, Ygal Haupt, Sudan He, David M. Heery, Michael O. Hengartner, Claudio Hetz, David A. Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jaeaettelae, Ana Janic, Bertrand Joseph, Philipp J. Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L. Kelly, Oliver Kepp, Adi Kimchi, Richard N. Kitsis, Daniel J. Klionsky, Ruth Kluck, Dmitri Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N. Lavrik, John J. Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A. Lipton, Richard A. Lockshin, Carlos Lopez-Otin, Tom Luedde, Marion MacFarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J. Martin, Jean-Claude Martinou, Pier G. Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A. Miao, Ute M. Moll, Cristina Munoz-Pinedo, Daniel J. Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Nunez, Andrew Oberst, Dimitry Ofengeim, Joseph T. Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M. Penninger, Francesca Pentimalli, David M. Pereira, Shazib Pervaiz, Marcus E. Peter, Paolo Pinton, Giovanni Porta, Jochen H. M. Prehn, Hamsa Puthalakath, Gabriel A. Rabinovich, Krishnaraj Rajalingam, Kodi S. Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M. P. Rodrigues, Barak Rotblat, Carla Rothlin, David C. Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M. Ryan, Kristopher A. Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S. Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R. Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W. G. Tait, Daolin Tang, Nektarios Tavernarakis, Carol M. Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G. Vander Heiden, Jacqueline L. Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia von Karstedt, Anne K. Voss, Karen H. Vousden, Domagoj Vucic, Daniela Vuri, Erwin F. Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E. Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi
Summary: Apoptosis is a regulated cell death process involving caspase family proteases. Inhibiting or delaying apoptosis experimentally through pharmacological and genetic strategies has demonstrated its importance in embryonic development, tissue homeostasis, and the pathogenesis of various human disorders. Defects in apoptotic cell death machinery impair development and promote oncogenesis, while inappropriate activation of apoptosis contributes to cell loss and tissue damage in neurological, cardiovascular, renal, hepatic, infectious, neoplastic, and inflammatory conditions.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Biochemistry & Molecular Biology
Gaia Pedriali, Daniela Ramaccini, Esmaa Bouhamida, Alessio Branchini, Giulia Turrin, Elisabetta Tonet, Antonella Scala, Simone Patergnani, Mirko Pinotti, Claudio Trapella, Carlotta Giorgi, Elena Tremoli, Gianluca Campo, Giampaolo Morciano, Paolo Pinton
Summary: The molecular composition and activity modulation of the permeability transition pore (PTP) have been extensively studied due to their importance in ischemia reperfusion injury (IRI). The c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and a target for cardioprotection. This study aims to identify equivalent residues in the human Csub sequence, validate their role in Oligomycin A-mediated PTP inhibition, and understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane derivatives as potential inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Tommaso Di Mambro, Giulia Pellielo, Esther Densu Agyapong, Marianna Carinci, Diego Chianese, Carlotta Giorgi, Giampaolo Morciano, Simone Patergnani, Paolo Pinton, Alessandro Rimessi
Summary: Mitochondria are essential for energy production and play important roles in various cell processes. They communicate with other organelles and cells through the release of mtDAMPs and interact with extracellular vesicles (EVs). EVs have emerged as important mediators of inter-cellular communication and can transport mitochondria and mtDAMPs to modulate metabolic and inflammatory responses in recipient cells. Further research is needed to fully understand the mechanisms and therapeutic potential of the relationship between EVs and mitochondria in inflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Giampaolo Morciano, Caterina Boncompagni, Daniela Ramaccini, Gaia Pedriali, Esmaa Bouhamida, Elena Tremoli, Carlotta Giorgi, Paolo Pinton
Summary: The most common alterations affecting mitochondria in cardiac pathological conditions include impairments of the electron transport chain activity, leading to a decrease in energy formation and ATP generation, as well as increased ROS generation and inflammation. These alterations contribute to the impairment of cardiac electrical characteristics, loss of myocyte contractility, and cardiomyocyte damage. The dysregulation of mitochondrial dynamics, which plays a role in maintaining mitochondrial fitness, is also observed in cardiac diseases. However, the translation and therapeutic applications of this knowledge are still in the early stages.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Maria Sofia Ciliento, Veronica Venturelli, Natale Schettini, Riccardo Bertola, Carlo Garaffoni, Giovanni Lanza, Roberta Gafa, Alessandro Borghi, Monica Corazza, Alen Zabotti, Sonia Missiroli, Caterina Boncompagni, Simone Patergnani, Mariasole Perrone, Carlotta Giorgi, Paolo Pinton, Marcello Govoni, Carlo Alberto Scire, Alessandra Bortoluzzi, Ettore Silvagni
Summary: The aim of this systematic literature review was to investigate the effects of b/tsDMARDs on the synovial membrane of PsA patients and identify biomarkers of response to therapy. A meta-analysis of 22 studies showed a significant reduction in CD3+ lymphocytes and CD68+ macrophages in synovial biopsies from patients treated with bDMARDs for 4-12 weeks. Reduction in CD3+ was correlated with clinical response. The most consistent finding in the literature was the reduction in CD3+/CD68+ sublining cells during the first 3 months of treatment with TNF inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Maria Livia Sassano, Alexander R. R. van Vliet, Ellen Vervoort, Sofie Van Eygen, Chris van den Haute, Benjamin Pavie, Joris Roels, Johannes V. V. Swinnen, Marco Spinazzi, Leen Moens, Kristina Casteels, Isabelle Meyts, Paolo Pinton, Saverio Marchi, Leila Rochin, Francesca Giordano, Blanca Felipe-Abrio, Patrizia Agostinis
Summary: ER-mitochondria appositions play a critical role in the transfer of ions and phospholipids between these organelles and impact mitochondrial bioenergetics. However, the molecular mechanisms involved in this process are not well understood. This study reveals that PERK acts as an adaptor to recruit the lipid transfer protein E-Syt1 at ER-mitochondria contact sites, enabling lipid transport and maintaining mitochondrial homeostasis. These findings provide insights into the molecular components and functions of the lipid trafficking machinery at ER-mitochondria contact sites.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Valentina Albanese, Sonia Missiroli, Mariasole Perrone, Martina Fabbri, Caterina Boncompagni, Salvatore Pacifico, Tiziano De Ventura, Antonella Ciancetta, Giulio Dondio, Franz Kricek, Paolo Pinton, Remo Guerrini, Delia Preti, Carlotta Giorgi
Summary: A series of aryl sulfonamide derivatives (ASDs) were designed and synthesized to inhibit the activation of the NLRP3 inflammasome. Compounds 6c, 7n, and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of other inflammasomes. These compounds were also found to reduce IL-1 beta production in vivo and attenuate melanoma tumor growth. The findings suggest that these potent NLRP3 inflammasome inhibitors could be considered for future therapeutic approaches in NLRP3 inflammasome-driven cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Angelo Di Vincenzo, Marnie Granzotto, Marika Crescenzi, Vincenzo Vindigni, Roberto Vettor, Marco Rossato
Summary: In this study, the effects of sex steroids on the expression of inflammatory mediators in human-derived adipocytes were evaluated. The results showed that non-aromatizable androgen DHT and the aromatase inhibitor anastrozole in combination with testosterone significantly enhanced the expression of inflammatory cytokines induced by LPS. These results confirm the involvement of sex hormones in adipose tissue inflammation and suggest a specific role for non-aromatizable androgens as amplificatory sex hormones of the inflammatory response.
Article
Cell Biology
Nada Dhaouadi, Veronica Angela Maria Vitto, Paolo Pinton, Lorenzo Galluzzi, Saverio Marchi
Summary: Multiple forms of regulated cell death (RCD) are associated with the activation of specific molecular mechanisms. Ca2+ ions can physically interact and regulate various components of the RCD machinery, leading to organellar dysfunction and increased sensitivity to cell death induced by other stressors.
Review
Biochemistry & Molecular Biology
Esmaa Bouhamida, Giampaolo Morciano, Gaia Pedriali, Daniela Ramaccini, Elena Tremoli, Carlotta Giorgi, Paolo Pinton, Simone Patergnani
Summary: Calcific aortic valve stenosis (CAVS) is a common cause of cardiovascular mortality, and its complex pathomechanisms are still being investigated. There is currently no effective treatment for CAVS, with surgical and transcatheter valve replacement being the only options. Hypoxia, inflammation, and mitochondrial impairments play significant roles in the development of CAVS. This review aims to explore the interplay between hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS pathogenesis, in order to better understand the molecular mechanisms and develop potential therapeutic approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Gokhan Burcin Kubat, Esmaa Bouhamida, Oner Ulger, Ibrahim Turkel, Gaia Pedriali, Daniela Ramaccini, Ozgur Ekinci, Berkay Ozerklig, Ozbeyen Atalay, Simone Patergnani, Beyza Nur Sahin, Giampaolo Morciano, Meltem Tuncer, Elena Tremoli, Paolo Pinton
Summary: Skeletal muscle is a dynamic and plastic tissue that plays a vital role in movement, posture, and force production. It functions as an endocrine organ capable of producing and secreting bioactive molecules. Various pathological conditions can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy.
Review
Biochemistry & Molecular Biology
Laura Palumbo, Marianna Carinci, Annunziata Guarino, Laila Asth, Silvia Zucchini, Sonia Missiroli, Alessandro Rimessi, Paolo Pinton, Carlotta Giorgi
Summary: Neuroinflammation is a defense mechanism in the central nervous system against harmful stimuli, but dysregulation of this process is associated with CNS disorders. It has been shown that neuroinflammation is linked to epilepsy, specifically the activation of the NLRP3 inflammasome and epileptic seizures. This review provides an overview of the role of NLRP3-dependent inflammation in epilepsy and proposes potential therapeutic strategies.