TY - JOUR AU - Nuernberg, Bernd AU - -Hammer, Sandra Beer AU - Reisinger, Ellen AU - Leiss, Veronika TI - Non-canonical G protein signaling JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 255 PY - 2024 PG - 22 SN - 0163-7258 DO - 10.1016/j.pharmthera.2024.108589 UR - https://m2.mtmt.hu/api/publication/34785746 ID - 34785746 N1 - Funding Agency and Grant Number: DFG-funded research training group (RTG); Deutsche Forschungsgemeinschaft (DFG) [464254052]; DFG [NU53/12-2, NU53/13-1]; Dr. Karl-Kuhn-Stiftung; Heisenberg program of the DFG [RE3174/2-1]; Cluster of Excellence iFIT [EXC2180]; University of Tubingen, Germany - DFG [EXC2180 - 390900677] Funding text: We thank Iris Noetzelmann, M.A., for her superb assistance in the preparation of the manuscript. We greatly appreciate the inspiring discussions with our RTG2816 colleagues. Our work presented in the manuscript has been financially supported by intramural starting grants to establish a DFG-funded research training group (RTG), and by the Deutsche Forschungsgemeinschaft (DFG) to RTG 2816 (grant number 464254052). B.N. is supported by DFG grants NU53/12-2 and NU53/13-1. V.L. received financial support by the Dr. Karl-Kuhn-Stiftung. E.R. is supported by the Heisenberg program of the DFG (RE3174/2-1). Further support came from the Cluster of Excellence iFIT (EXC2180) to S.B.-H., University of Tubingen, Germany, funded by the DFG under Germany's Excellence Strategies-EXC2180 - 390900677. All Figures were created with BioRender.com. AB - The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like BARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined "activators of G protein signaling" (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (Gi) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions. (c) 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). LA - English DB - MTMT ER - TY - JOUR AU - Yamahara, K. AU - Yasuda-Yamahara, M. AU - Kume, S. TI - A novel therapeutic target for kidney diseases: Lessons learned from starvation response JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 254 PY - 2024 SN - 0163-7258 DO - 10.1016/j.pharmthera.2024.108590 UR - https://m2.mtmt.hu/api/publication/34777781 ID - 34777781 N1 - Export Date: 8 April 2024 CODEN: PHTHD LA - English DB - MTMT ER - TY - JOUR AU - You, Y. AU - Chen, Z. AU - Hu, W.-W. TI - The role of microglia heterogeneity in synaptic plasticity and brain disorders: Will sequencing shed light on the discovery of new therapeutic targets? JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 255 PY - 2024 SN - 0163-7258 DO - 10.1016/j.pharmthera.2024.108606 UR - https://m2.mtmt.hu/api/publication/34766123 ID - 34766123 N1 - Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, China Export Date: 3 April 2024 CODEN: PHTHD Correspondence Address: Hu, W.-W.; Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, China; email: huww@zju.edu.cn Funding details: National Key Research and Development Program of China, NKRDPC, 2020YFA0803900, 2021ZD0202800 Funding text 1: We are very grateful to Genesis Tech Communication company for language editing. This work was supported by the National Key R&D Program of China No. 2020YFA0803900 and STI2030-Major Projects (Grant No. 2021ZD0202800 ). AB - Microglia play a crucial role in interacting with neuronal synapses and modulating synaptic plasticity. This function is particularly significant during postnatal development, as microglia are responsible for removing excessive synapses to prevent neurodevelopmental deficits. Dysregulation of microglial synaptic function has been well-documented in various pathological conditions, notably Alzheimer's disease and multiple sclerosis. The recent application of RNA sequencing has provided a powerful and unbiased means to decipher spatial and temporal microglial heterogeneity. By identifying microglia with varying gene expression profiles, researchers have defined multiple subgroups of microglia associated with specific pathological states, including disease-associated microglia, interferon-responsive microglia, proliferating microglia, and inflamed microglia in multiple sclerosis, among others. However, the functional roles of these distinct subgroups remain inadequately characterized. This review aims to refine our current understanding of the potential roles of heterogeneous microglia in regulating synaptic plasticity and their implications for various brain disorders, drawing from recent sequencing research and functional studies. This knowledge may aid in the identification of pathogenetic biomarkers and potential factors contributing to pathogenesis, shedding new light on the discovery of novel drug targets. The field of sequencing-based data mining is evolving toward a multi-omics approach. With advances in viral tools for precise microglial regulation and the development of brain organoid models, we are poised to elucidate the functional roles of microglial subgroups detected through sequencing analysis, ultimately identifying valuable therapeutic targets. © 2024 Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - Salloum-Asfar, Salam AU - Zawia, Nasser AU - Abdulla, Sara A. TI - Retracing our steps: A review on autism research in children, its limitation and impending pharmacological interventions JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 253 PY - 2024 PG - 10 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108564 UR - https://m2.mtmt.hu/api/publication/34638580 ID - 34638580 LA - English DB - MTMT ER - TY - JOUR AU - Isshiki, Takuma AU - Naiel, Safaa AU - Vierhout, Megan AU - Otsubo, Kohei AU - Ali, Pareesa AU - Tsubouchi, Kazuya AU - Yazdanshenas, Parichehr AU - Kumaran, Vaishnavi AU - Dvorkin-Gheva, Anna AU - Kolb, Martin R. J. AU - Ask, Kjetil TI - Therapeutic strategies to target connective tissue growth factor in fibrotic lung diseases JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 253 PY - 2024 PG - 13 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108578 UR - https://m2.mtmt.hu/api/publication/34611544 ID - 34611544 N1 - Export Date: 28 February 2024; CODEN: PHTHD AB - The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-beta. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach. (c) 2023 Elsevier Inc. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Honan, Lauren E. AU - Fraser-Spears, Rheaclare AU - Daws, Lynette C. TI - Organic cation transporters in psychiatric and substance use disorders JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 253 PY - 2024 PG - 24 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108574 UR - https://m2.mtmt.hu/api/publication/34589146 ID - 34589146 AB - Psychiatric and substance use disorders inflict major public health burdens worldwide. Their widespread burden is compounded by a dearth of effective treatments, underscoring a dire need to uncover novel therapeutic targets. In this review, we summarize the literature implicating organic cation transporters (OCTs), including three subtypes of OCTs (OCT1, OCT2, and OCT3) and the plasma membrane monoamine transporter (PMAT), in the neurobiology of psychiatric and substance use disorders with an emphasis on mood and anxiety disorders, alcohol use disorder, and psychostimulant use disorder. OCTs transport monoamines with a low affinity but high capacity, situating them to play a central role in regulating monoamine homeostasis. Preclinical evidence discussed here suggests that OCTs may serve as promising targets for treatment of psychiatric and substance use disorders and encourage future research into their therapeutic potential.(c) 2023 Published by Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - Yadav, Poonam AU - Singh, Sumeet Kumar AU - Rajput, Sonu AU - Allawadhi, Prince AU - Khurana, Amit AU - Weiskirchen, Ralf AU - Navik, Umashanker TI - Therapeutic potential of stem cells in regeneration of liver in chronic liver diseases: Current perspectives and future challenges JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 253 PY - 2024 PG - 23 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108563 UR - https://m2.mtmt.hu/api/publication/34585655 ID - 34585655 AB - The deposition of extracellular matrix and hyperplasia of connective tissue characterizes chronic liver disease called hepatic fibrosis. Progression of hepatic fibrosis may lead to hepatocellular carcinoma. At this stage, only liver transplantation is a viable option. However, the number of possible liver donors is less than the number of patients needing transplantation. Consequently, alternative cell therapies based on non-stem cells (e.g., fibroblasts, chondrocytes, keratinocytes, and hepatocytes) therapy may be able to postpone hepatic disease, but they are often ineffective. Thus, novel stem cell-based therapeutics might be potentially important cutting-edge approaches for treating liver diseases and reducing patient' suffering. Several signaling pathways provide targets for stem cell interventions. These include pathways such as TGF-beta, STAT3/BCL-2, NADPH oxidase, Raf/MEK/ ERK, Notch, and Wnt/beta-catenin. Moreover, mesenchymal stem cells (MSCs) stimulate interleukin (IL)-10, which inhibits T-cells and converts M1 macrophages into M2 macrophages, producing an anti-inflammatory environment. Furthermore, it inhibits the action of CD4+ and CD8+ T cells and reduces the activity of TNF-alpha and interferon cytokines by enhancing IL-4 synthesis. Consequently, the immunomodulatory and antiinflammatory capabilities of MSCs make them an attractive therapeutic approach. Importantly, MSCs can inhibit the activation of hepatic stellate cells, causing their apoptosis and subsequent promotion of hepatocyte proliferation, thereby replacing dead hepatocytes and reducing liver fibrosis. This review discusses the multidimensional therapeutic role of stem cells as cell-based therapeutics in liver fibrosis. LA - English DB - MTMT ER - TY - JOUR AU - Mushtaq, A. AU - Wu, P. AU - Naseer, M.M. TI - Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 254 PY - 2024 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108579 UR - https://m2.mtmt.hu/api/publication/34535454 ID - 34535454 N1 - Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Otto-Hahn Str. 11, Dortmund, 44227, Germany Export Date: 26 January 2024 CODEN: PHTHD Correspondence Address: Naseer, M.M.; Department of Chemistry, Pakistan; email: moazzam@qau.edu.pk Funding details: Alexander von Humboldt-Stiftung, AvH Funding details: Quaid-i-Azam University, QAU Funding text 1: We are grateful to the Quaid-i-Azam University for funding through University Research Fund (URF) . MMN is grateful to the Alexander von Humboldt (AvH) foundation for funding under the program “Renewed Research Stays in Germany”. AB - Cancer, a noncommunicable disease, is the leading cause of mortality worldwide and is anticipated to rise by 75% in the next two decades, reaching approximately 25 million cases. Traditional cancer treatments, such as radiotherapy and surgery, have shown limited success in reducing cancer incidence. As a result, the focus of cancer chemotherapy has switched to the development of novel small molecule antitumor agents as an alternate strategy for combating and managing cancer rates. Heterocyclic compounds are such agents that bind to specific residues in target proteins, inhibiting their function and potentially providing cancer treatment. This review focuses on privileged heterocyclic pharmacophores with potent activity against carbonic anhydrases and kinases, which are important anticancer targets. Evaluation of ongoing pre-clinical and clinical research of heterocyclic compounds with potential therapeutic value against a variety of malignancies as well as the provision of a concise summary of the role of heterocyclic scaffolds in various chemotherapy protocols have also been discussed. The main objective of the article is to highlight key heterocyclic scaffolds involved in recent anticancer drug design that demands further attention from the drug development community to find more effective and safer targeted small-molecule anticancer agents. © 2023 Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - Weyer, M.-P. AU - Strehle, J. AU - Schäfer, M.K.E. AU - Tegeder, I. TI - Repurposing of pexidartinib for microglia depletion and renewal JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 253 PY - 2024 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108565 UR - https://m2.mtmt.hu/api/publication/34493845 ID - 34493845 N1 - Institute of Clinical Pharmacology, Goethe-University Frankfurt, Faculty of Medicine, Frankfurt, Germany Department of Anesthesiology, University Medical Center Johannes Gutenberg-University Mainz, Germany Export Date: 10 January 2024 CODEN: PHTHD Correspondence Address: Tegeder, I.; Institute of Clinical Pharmacology, Theodor Stern Kai 7 (Bd. 74-75), Germany; email: tegeder@em.uni-frankfurt.de Funding details: Deutsche Forschungsgemeinschaft, DFG, CRC1080 C02, TE 322/11-1 Funding text 1: The work was supported by the Deutsche Forschungsgemeinschaft ( CRC1080 C02 to IT and TE 322/11-1 to IT). The funding institution had no role in data collection, analysis, preparation of the manuscript or decision to publish. AB - Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1–2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach. © 2023 Elsevier Inc. LA - English DB - MTMT ER - TY - JOUR AU - Tengesdal, Isak W. AU - Dinarello, Charles A. AU - Marchetti, Carlo TI - NLRP3 and cancer: Pathogenesis and therapeutic opportunities JF - PHARMACOLOGY & THERAPEUTICS J2 - PHARMACOL THERAPEUT VL - 251 PY - 2023 PG - 18 SN - 0163-7258 DO - 10.1016/j.pharmthera.2023.108545 UR - https://m2.mtmt.hu/api/publication/34626085 ID - 34626085 N1 - Export Date: 28 February 2024; CODEN: PHTHD LA - English DB - MTMT ER -