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Targeting Fks1 proteins for novel antifungal drug discovery Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-03-15 Vinit Kumar, Juan Huang, Yawen Dong, Ge-Fei Hao
Fungal infections are a major threat to human health. The limited availability of antifungal drugs, the emergence of drug resistance, and a growing susceptible population highlight the critical need for novel antifungal agents. The enzymes involved in fungal cell wall synthesis offer potential targets for antifungal drug development. Recent studies have enhanced our focus on the enzyme Fks1, which
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Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-03-12 Mari J. Jokinen, Panu K. Luukkonen
Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress
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Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-03-07 Mirza Ahmar Beg, Minqi Huang, Lance Vick, K.N. Shashanka Rao, Jue Zhang, Yiliang Chen
Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However
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Translational adaptation in breast cancer metastasis and emerging therapeutic opportunities Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-03-06 Siyu Chen, Albertas Navickas, Hani Goodarzi
Breast cancer’s tendency to metastasize poses a critical barrier to effective treatment, making it a leading cause of mortality among women worldwide. A growing body of evidence is showing that translational adaptation is emerging as a key mechanism enabling cancer cells to thrive in the dynamic tumor microenvironment (TME). Here, we systematically summarize how breast cancer cells utilize translational
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VMAT structures reveal exciting targets for drug development Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-29 Shimon Schuldiner, Lucy R. Forrest
Vesicular monoamine transporter (VMAT)-2 has a crucial role in the neurotransmission of biogenic amines. Recently, , , , and individually reported cryo-electron microscopy (EM) structures of human VMAT2, offering opportunities for developing improved therapeutics and deep insights into the functioning of this protein.
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Mitochondrial DNA competition: starving out the mutant genome Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-23 Antonella Spinazzola, Diego Perez-Rodriguez, Jan Ježek, Ian J. Holt
High levels of pathogenic mitochondrial DNA (mtDNA) variants lead to severe genetic diseases, and the accumulation of such mutants may also contribute to common disorders. Thus, selecting against these mutants is a major goal in mitochondrial medicine. Although mutant mtDNA can drift randomly, mounting evidence indicates that active forces play a role in the selection for and against mtDNA variants
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Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-20 Jeffrey White, Frederick A. Derheimer, Kristen Jensen-Pergakes, Shawn O’Connell, Shikhar Sharma, Noah Spiegel, Thomas A. Paul
Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs
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Recent advances in generative biology for biotherapeutic discovery Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-19 Marissa Mock, Christopher James Langmead, Peter Grandsard, Suzanne Edavettal, Alan Russell
Generative biology combines artificial intelligence (AI), advanced life sciences technologies, and automation to revolutionize the process of designing novel biomolecules with prescribed properties, giving drug discoverers the ability to escape the limitations of biology during the design of next-generation protein therapeutics. Significant hurdles remain, namely: (i) the inherently complex nature
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Alzheimer’s therapeutic development: shifting neurodegeneration to neuroregeneration Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-14 Miao-Kun Sun, Daniel L. Alkon
Alzheimer’s disease (AD), similar to AD-related dementias, is characterized by impaired/lost neuronal structures and functions due to a long progression of neurodegeneration. Derailed endogenous signal pathways and disease processes have critical roles in neurodegeneration and are pharmacological targets in inducing neuroregeneration. Pharmacologically switching/shifting the brain status from neurodegeneration
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Targeting chromosomal instability and aneuploidy in cancer Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-13 Sugandha Bhatia, Kum Kum Khanna, Pascal H.G. Duijf
Cancer development and therapy resistance are driven by chromosomal instability (CIN), which causes chromosome gains and losses (i.e., aneuploidy) and structural chromosomal alterations. Technical limitations and knowledge gaps have delayed therapeutic targeting of CIN and aneuploidy in cancers. However, our toolbox for creating and studying aneuploidy in cell models has greatly expanded recently.
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The role of NMR in advancing small molecule drug discovery Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-13 Leszek Poppe
Navigating the ever-evolving landscape of nuclear magnetic resonance (NMR) poses challenges for the industry. This work explores promising approaches that illuminate protein–ligand interactions in the context of structural dynamics, facilitating targeted drug discovery. I acknowledge existing limitations and highlight future opportunities, which may pave the way for broader NMR integration and faster
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Advances in inhibitor development targeting the PWWP domain Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-09 Yunyuan Huang, Yanxi Li, Jinrong Min
The PWWP domain binds to both histone and DNA of a nucleosome in a bivalent way. PWWP domain-containing proteins are involved in different biological processes, and their aberrant expression is implicated in various human diseases. Here, we discuss the recent developments and challenges in targeting the PWWP domain for therapeutic intervention.
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Advisory Board and Contents Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-01
Abstract not available
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Subscription and Copyright Information Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-02-01
Abstract not available
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Complex architecture of cardiac muscle thick filaments revealed Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-31 Pradeep K. Luther, Steve B. Marston
Muscle contraction is orchestrated by the well-understood thin filaments and the markedly complex thick filaments. Studies by . and , discussed here, have unravelled the structure of the mammalian heart thick filament in exquisite near-atomic detail and pave the way for understanding physiological modulation pathways and mutation-induced dysfunction and for designing potential drugs to modify defects
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The structure and function of olfactory receptors Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-31 Chenyang Wu, Marc Xu, Junlin Dong, Wenqiang Cui, Shuguang Yuan
Olfactory receptors (ORs) form the most important chemosensory receptor family responsible for our sense of smell in the nasal olfactory epithelium. This receptor family belongs to the class A G protein-coupled receptors (GPCRs). Recent research has indicated that ORs are involved in many nonolfactory physiological processes in extranasal tissue, such as the brain, pancreas, and testes, and implies
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Glymphatic-stagnated edema induced by traumatic brain injury Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-29 Per Kristian Eide, Geir Ringstad
Traumatic brain injury (TBI) outcomes are notably affected by brain edema. A recent report by Hussain et al. unveils a unique form, glymphatic-stagnated brain edema, that stems from impaired glymphatic and lymphatic drainage induced by noradrenergic activation. Consequently, pan-noradrenergic inhibition may emerge as an innovative treatment for TBI-related edema, challenging traditional therapeutic
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Mirikizumab (Omvoh™) for ulcerative colitis Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-22 Alexander Hammerhøj, Theresa Louise Boye, Ebbe Langholz, Ole Haagen Nielsen
Abstract not available
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Revisiting sensitivity of senescent cells to BH3 mimetics Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-20 Nadine Martin, Anda Huna, Athanasios Tsalikis, David Bernard
B cell leukemia/lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics were reported to selectively kill senescent cells and improve age-related diseases. Defining why these cells show increased sensitivity to these molecules will help to identify new pharmacological compounds with senolytic activity. Here, we discuss how recent research findings provide new clues to understand this vulnerability.
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Context-dependent role of SIRT3 in cancer Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-19 Jin Zhang, Jing Ye, Shiou Zhu, Bo Han, Bo Liu
Sirtuin 3 (SIRT3), an NAD+-dependent deacetylase, plays a key role in the modulation of metabolic reprogramming and regulation of cell death, as well as in shaping tumor phenotypes. Owing to its critical role in determining tumor-type specificity or the direction of tumor evolution, the development of small-molecule modulators of SIRT3, including inhibitors and activators, is of significant interest
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Leveraging spatial omics for the development of precision sarcoma treatments Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-11 Cui Tu, Arutha Kulasinghe, Andrew Barbour, Fernando Souza-Fonseca-Guimaraes
Sarcomas are rare and heterogeneous cancers that arise from bone or soft tissue, and are the second most prevalent solid cancer in children and adolescents. Owing to the complex nature of pediatric sarcomas, the development of therapeutics for pediatric sarcoma has seen little progress in the past decades. Existing treatments are largely limited to chemotherapy, radiation, and surgery. Limited knowledge
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Emerging epigenetic insights into aging mechanisms and interventions Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-11 Zeming Wu, Weiqi Zhang, Jing Qu, Guang-Hui Liu
Epigenetic dysregulation emerges as a critical hallmark and driving force of aging. Although still an evolving field with much to explore, it has rapidly gained significance by providing valuable insights into the mechanisms of aging and potential therapeutic opportunities for age-related diseases. Recent years have witnessed remarkable strides in our understanding of the epigenetic landscape of aging
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Do the therapeutic effects of psilocybin involve actions in the gut? Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-11 Felicia Reed, Claire J. Foldi
The psychedelic compound psilocybin has recently emerged as a therapeutic intervention for various mental health conditions. Psilocybin is a potent agonist of serotonin (5-HT) receptors (5-HTRs), which are expressed in the brain and throughout peripheral tissues, with particularly high expression in the gastrointestinal (GI) tract. However, no studies have investigated the possibility that peripheral
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Tumor iron homeostasis and immune regulation Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-11 Yan-Yu Zhang, Yi Han, Wen-Ning Li, Rui-Hua Xu, Huai-Qiang Ju
Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism
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Subscription and Copyright Information Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-04
Abstract not available
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Advisory Board and Contents Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-04
Abstract not available
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Metabolite-sensing GPCRs in rheumatoid arthritis Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2024-01-05 Xuezhi Yang, Wankang Zhang, Luping Wang, Yingjie Zhao, Wei Wei
Persistent inflammation in damaged joints results in metabolic dysregulation of the synovial microenvironment, causing pathogenic alteration of cell activity in rheumatoid arthritis (RA). Recently, the role of metabolite and metabolite-sensing G protein-coupled receptors (GPCRs) in the RA-related inflammatory immune response (IIR) has become a focus of research attention. These GPCRs participate in
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Harnessing deep learning for enhanced ligand docking Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-30 Xujun Zhang, Chao Shen, Chang-Yu Hsieh, Tingjun Hou
Ligand docking (LD), a technology for predicting protein–ligand (PL)-binding conformations and strengths, plays key roles in virtual screening (VS). However, the accuracy and speed of current LD methodologies remain suboptimal. Here, we discuss how deep learning (DL) could help to bridge this gap by examining recent advancements and projecting future trends.
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The rise of epitranscriptomics: recent developments and future directions Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-15 Jonas Cerneckis, Guo-Li Ming, Hongjun Song, Chuan He, Yanhong Shi
The epitranscriptomics field has undergone tremendous growth since the discovery that the RNA N6-methyladenosine (m6A) modification is reversible and is distributed throughout the transcriptome. Efforts to map RNA modifications transcriptome-wide and reshape the epitranscriptome in disease settings have facilitated mechanistic understanding and drug discovery in the field. In this review we discuss
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Spatial pharmacology using mass spectrometry imaging Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-15 Presha Rajbhandari, Taruna V. Neelakantan, Noreen Hosny, Brent R. Stockwell
The emerging and powerful field of spatial pharmacology can map the spatial distribution of drugs and their metabolites, as well as their effects on endogenous biomolecules including metabolites, lipids, proteins, peptides, and glycans, without the need for labeling. This is enabled by mass spectrometry imaging (MSI) that provides previously inaccessible information in diverse phases of drug discovery
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Pharmacological targets at the lysosomal autophagy–NLRP3 inflammasome crossroads Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-14 Srinivasa Reddy Bonam, Dylan Mastrippolito, Philippe Georgel, Sylviane Muller
Many aspects of cell homeostasis and integrity are maintained by the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome. The NLRP3 oligomeric protein complex assembles in response to exogenous and endogenous danger signals. This inflammasome has also been implicated in the pathogenesis of a range of disease conditions, particularly
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Biomarkers and targeted therapy for cancer stem cells Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-09 Yusheng Liu, Hua Wang
Cancer stem cells (CSCs) are a small subpopulation of cancer cells with capabilities of self-renewal, differentiation, and tumorigenicity, and play a critical role in driving tumor heterogeneity that evolves insensitivity to therapeutics. For these reasons, extensive efforts have been made to identify and target CSCs to potentially improve the antitumor efficacy of therapeutics. While progress has
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Computational and artificial intelligence-based approaches for drug metabolism and transport prediction Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-09 Balint Dudas, Maria A. Miteva
Drug metabolism and transport, orchestrated by drug-metabolizing enzymes (DMEs) and drug transporters (DTs), are implicated in drug–drug interactions (DDIs) and adverse drug reactions (ADRs). Reliable and precise predictions of DDIs and ADRs are critical in the early stages of drug development to reduce the rate of drug candidate failure. A variety of experimental and computational technologies have
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PPAR agonists for the treatment of neuroinflammatory diseases Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-12-07 Celene Titus, Md Tozammel Hoque, Reina Bendayan
Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid homeostasis, have recently received significant attention due to their additional anti-inflammatory and neuroprotective effects. Several newly developed PPAR agonists have shown high selectivity for specific PPAR isoforms in vitro and in vivo
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Advisory Board and Contents Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-11-16
Abstract not available
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Targeting sensory neuron GPCRs for peripheral neuropathic pain Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-11-11 Ankit Uniyal, Vinod Tiwari, Takashi Tsukamoto, Xinzhong Dong, Yun Guan, Srinivasa N. Raja
Despite the high prevalence of peripheral neuropathic pain (NP) conditions and significant progress in understanding its underlying mechanisms, the management of peripheral NP remains inadequate. Existing pharmacotherapies for NP act primarily on the central nervous system (CNS) and are often associated with CNS-related adverse effects, limiting their clinical effectiveness. Mounting preclinical evidence
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Subscription and Copyright Information Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-11-16
Abstract not available
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A quick guide to networking for scientists Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-11-13 Heather K. Beasley, Ky’Era V. Acktins, Andrea G. Marshall, Edgar Garza-Lopez, Celestine Wanjalla, Estevão Scudese, Annet Kirabo, Kaihua Liu, Antentor Hinton
Networking is an important skill for finding social relationships relevant to one’s career. However, networking can be difficult to navigate as different social situations and career levels require unique skill sets. Here, we provide tips for effective networking at conferences, dinners, and other events.
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Cancer drug repurposing in autism spectrum disorder Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-11-06 Giorgia Pedini, Chin-Lin Chen, Tilmann Achsel, Claudia Bagni
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Genetic diversity complicates drug development. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared
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Ligand selectivity hotspots in serotonin GPCRs Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-31 Icaro A. Simon, Walden E. Bjørn-Yoshimoto, Kasper Harpsøe, Stylianos Iliadis, Bo Svensson, Anders A. Jensen, David E. Gloriam
Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition
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Emerging approaches to induce immune tolerance to therapeutic proteins Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-29 Justine C. Noel, Daniel Lagassé, Basil Golding, Zuben E. Sauna
Immunogenicity affects the safety and efficacy of therapeutic proteins. This review is focused on approaches for inducing immunological tolerance to circumvent the immunogenicity of therapeutic proteins in the clinic. The few immune tolerance strategies that are used in the clinic tend to be inefficient and expensive and typically involve global immunosuppression, putting patients at risk of infections
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Potential therapeutic targets for trauma management Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-27 Zizheng Li, Ou Qiao, Yuru Wang, Ning Li, Yanhua Gong
Despite advances in medical treatments for severe trauma, it remains a critical condition associated with high mortality. During trauma, the release of endogenous damage-associated molecular patterns (DAMPs) can induce immune dysfunction, leading to sepsis or multiple organ dysfunction syndrome (MODS). Vaccines based on specific pathogen antigens and pathogen-associated molecular patterns (PAMPs) contribute
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m6A epitranscriptomic modification in diabetic microvascular complications Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-27 Li-Chan Lin, Zhi-Yan Liu, Jing-Jing Yang, Jian-Yuan Zhao, Hui Tao
N6-methyladenosine (m6A) modifications are modulated by m6A methyltransferases, m6A demethylases, and m6A-binding proteins. The dynamic and reversible patterns of m6A modification control cell fate programming by regulating RNA splicing, translation, and decay. Emerging evidence demonstrates that m6A modification of coding and noncoding RNAs exerts crucial effects that influence the pathogenesis of
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New tricks for an old pathway: emerging Notch-based biotechnologies and therapeutics Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-25 Elliot Medina, David H. Perez, Daniel Antfolk, Vincent C. Luca
The Notch pathway regulates a diverse array of cell fate decisions, making it an enticing target in cancer therapy and regenerative medicine. During the early stages of Notch drug development, off-target toxicity precluded the approval of Notch inhibitors for the treatment of cancer. However, recent advances in our understanding of Notch structure and signaling have led to the development of several
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Glaucoma: neuroprotection with NAD-based therapeutic interventions Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-23 Alberto Chiarugi
Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs) represents a key therapeutic target. Unfortunately, failure of clinical trials with neuroprotective agents, in particular those testing the anti-excitotoxic drug memantine, generated widespread skepticism regarding the possibility
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Development of bispecific T cell engagers: harnessing quantitative systems pharmacology Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-17 Timothy Qi, Xiaozhi Liao, Yanguang Cao
Bispecific T cell engagers (bsTCEs) have emerged as a promising class of cancer immunotherapy. Several bsTCEs have achieved marketing approval; dozens more are under clinical investigation. However, the clinical development of bsTCEs remains rife with challenges, including nuanced pharmacology, limited translatability of preclinical findings, frequent on-target toxicity, and convoluted dosing regimens
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Advisory Board and Contents Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-12
Abstract not available
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Advancing targeted protein degradation modalities Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-12 Jerry C. Madukwe
Abstract not available
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Celiac disease: mechanisms and emerging therapeutics Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-14 Harrison A. Besser, Chaitan Khosla
Celiac disease (CeD) is a widespread, gluten-induced, autoimmune disorder that lacks any medicinal therapy. Towards the goal of developing non-dietary treatments for CeD, research has focused on elucidating its molecular and cellular etiology. A model of pathogenesis has emerged centered on interactions between three molecular families: specific class II MHC proteins on antigen-presenting cells (APCs)
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Exploring host–virus interaction to improve immunotherapy against Ebola virus Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-14 Dacquin M. Kasumba, John Misasi, Sabue Mulangu, Placide Mbala-Kingebeni
Recent immunological advances have led to the development of FDA-approved immunotherapies against Ebola virus (EBOV). However, patients with high viral loads have not seen as large a benefit as mild cases. Here we discuss areas of investigation that may lead to adjunctive immune therapy for patients with severe EBOV disease.
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Subscription and Copyright Information Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-10-12
Abstract not available
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Unravelling the signaling power of pollutants Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-30 Ana L. Manzano-Covarrubias, Hong Yan, Minh D.A. Luu, Phoeja S. Gadjdjoe, Amalia M. Dolga, Martina Schmidt
Exposure to environmental pollutants contributes to diverse pathologies, including pulmonary disease, lower respiratory infections, cancer, and stroke. Pollutants’ entry can occur through inhalation, traversing endothelial and epithelial barriers, and crossing the blood–brain barrier, leading to a wide distribution throughout the human body via systemic circulation. Pollutants cause cellular damage
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Structural asymmetry in FGF23 signaling Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-29 Shih-Hsien Liu, Zhousheng Xiao, Jeremy C. Smith, L. Darryl Quarles
Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor (FGFR), α-Klotho, and heparin sulfate. These structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling.
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Proteomic approaches advancing targeted protein degradation Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-29 Gajanan Sathe, Gopal P. Sapkota
Targeted protein degradation (TPD) is an emerging modality for research and therapeutics. Most TPD approaches harness cellular ubiquitin-dependent proteolytic pathways. Proteolysis-targeting chimeras (PROTACs) and molecular glue (MG) degraders (MGDs) represent the most advanced TPD approaches, with some already used in clinical settings. Despite these advances, TPD still faces many challenges, pertaining
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The promise of targeted protein degradation approaches Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-28 Danette L. Daniels, Gopal P. Sapkota, Lyn H. Jones
Abstract not available
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Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-26 Camilla Scarpellini, Greta Klejborowska, Caroline Lanthier, Behrouz Hassannia, Tom Vanden Berghe, Koen Augustyns
Ferroptosis is an iron-catalysed form of regulated cell death, which is critically dependent on phospholipid peroxidation of cellular membranes. Ferrostatin 1 was one of the first synthetic radical-trapping antioxidants (RTAs) reported to block ferroptosis and it is widely used as reference compound. Ferroptosis has been linked to multiple diseases and the use of its inhibitors could have therapeutic
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Covalent fragment approaches targeting non-cysteine residues Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-26 Noémi Csorba, Péter Ábrányi-Balogh, György M. Keserű
Covalent fragment approaches combine advantages of covalent binders and fragment-based drug discovery (FBDD) for target identification and validation. Although early applications focused mostly on cysteine labeling, the chemistries of available warheads that target other orthosteric and allosteric protein nucleophiles has recently been extended. The range of different warheads and labeling chemistries
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Harnessing UBR5 for targeted protein degradation of key transcriptional regulators Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-26 Asad M. Taherbhoy, Danette L. Daniels
Targeted protein degradation (TPD) has opened the door for drugging transcriptional regulators, yet the number of proteins targeted and E3 ligases utilized remain limited. Here, we highlight UBR5 and propose multiple strategies by which this E3 ligase could be modulated to drive degradation of key transcriptional targets implicated in disease.
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Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-26 Shambhavi Borde, Sandro Matosevic
The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated
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Lighting the way to tumor destruction Trends Pharmacol. Sci. (IF 13.8) Pub Date : 2023-09-25 Christina C. Kuismi, Behnam Nabet
Achieving tumor-specific protein loss remains a challenge in the delivery of proteolysis-targeting chimeras (PROTACs) as cancer therapeutics. As a solution, Wang et al. recently developed nanoformulated PROTACs (NAPs), a novel photoactivatable degradation approach. This innovative class of compounds harnesses near-infrared (NIR) light for precise PROTAC release and protein degradation in mouse tumors