Pub Date : 2025-02-01DOI: 10.1016/j.pharmthera.2024.108785
Habiba Ramzan , Dilara Abbas Bukhari , Zuhra Bibi , Arifullah , Isha , Atif Nawaz , Abdul Rehman
Polycystic Ovarian Syndrome is one of the major prevalent causes of infertility reported worldwide nearly 6–26 %, especially in girls hitting puberty and women at their childbearing age. The main clinical manifestations include irregular menstrual cycle, small cysts on one or both ovaries, chronic oligo-anovulation, and hirsutism. The etiological criteria are very complex and related to many factors like obesity, insulin sensitivity, inflammation, hyperandrogenism, diabetes mellitus type II, cardiovascular diseases, and dysbiosis of gut microbiota. The given review focuses on managing PCOS through probiotics by analyzing the effects on the symptoms of the disease. The probiotics effective in treating PCOS belong to Bifidobacterium, Lactobacilli, Clostridium, Enterococcus, and other Lactic acid bacteria. Its significance in PCOS is mainly due to the antagonizing of the growth of pathogenic microorganisms, increasing intestinal mucus layer production, reducing intestinal permeability, and modulating the gastrointestinal immune system. Also, their interaction with certain hormones such as insulin, androgen, and estrogen through short-chain fatty acids influences fertility. More research is necessary to validate these results. Probiotic supplements could be a viable option for treating PCOS in adults.
{"title":"Probiotic supplement for the treatment of polycystic ovarian syndrome","authors":"Habiba Ramzan , Dilara Abbas Bukhari , Zuhra Bibi , Arifullah , Isha , Atif Nawaz , Abdul Rehman","doi":"10.1016/j.pharmthera.2024.108785","DOIUrl":"10.1016/j.pharmthera.2024.108785","url":null,"abstract":"<div><div>Polycystic Ovarian Syndrome is one of the major prevalent causes of infertility reported worldwide nearly 6–26 %, especially in girls hitting puberty and women at their childbearing age. The main clinical manifestations include irregular menstrual cycle, small cysts on one or both ovaries, chronic oligo-anovulation, and hirsutism. The etiological criteria are very complex and related to many factors like obesity, insulin sensitivity, inflammation, hyperandrogenism, diabetes mellitus type II, cardiovascular diseases, and dysbiosis of gut microbiota. The given review focuses on managing PCOS through probiotics by analyzing the effects on the symptoms of the disease. The probiotics effective in treating PCOS belong to <em>Bifidobacterium, Lactobacilli, Clostridium, Enterococcus,</em> and other Lactic acid bacteria. Its significance in PCOS is mainly due to the antagonizing of the growth of pathogenic microorganisms, increasing intestinal mucus layer production, reducing intestinal permeability, and modulating the gastrointestinal immune system. Also, their interaction with certain hormones such as insulin, androgen, and estrogen through short-chain fatty acids influences fertility. More research is necessary to validate these results. Probiotic supplements could be a viable option for treating PCOS in adults.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108785"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gastrointestinal tract (GIT) plays a pivotal role in the absorption of orally administered drugs, with the small intestine serving as the primary site due to its extensive surface area and specialized cell types, including enterocytes and M cells. After oral administration, drugs are generally transported via the portal vein to the liver, where they undergo first-pass metabolism. This process involves various enzymatic reactions, including glucuronidation, facilitated by uridine diphosphate-glucuronosyltransferase (UGT), a major phase 2 reaction in mammalian metabolism.
UGTs conjugate glucuronic acid to a wide array of endogenous and exogenous substrates, enhancing their solubility and excretion, but significantly affecting the bioavailability and therapeutic efficacy of drugs. UGT enzymes are ubiquitously distributed across tissues, prominently in the liver, but also in the GIT, kidneys, brain, and other organs where they play crucial roles in xenobiotic metabolism.
Species-specific differences in UGT expression and activity impact the selection of animal models for pharmacological studies. Various experimental models – ranging from computational simulations (in silico) to laboratory experiments (in vitro) and animal studies (in vivo) – are employed throughout drug discovery and development to evaluate drug metabolism, including UGT activity.
Effective strategies to counter pre-systemic metabolism are critical for improving drug bioavailability. This review explores several approaches including prodrugs, co-administration of specific molecules or use of inhibiting excipients in formulations. Strategies incorporating these excipients in nanoformulations demonstrate notable increases in drug absorption and bioavailability.
This review highlights the importance of targeted delivery systems and excipient selection in overcoming metabolic barriers, aiming to optimize drug efficacy and patient outcomes.
{"title":"Glucuronidation of orally administered drugs and the value of nanocarriers in strategies for its overcome","authors":"Laura Hervieu , Anne-Claire Groo , Jérémy Bellien , Dominique Guerrot , Aurélie Malzert-Fréon","doi":"10.1016/j.pharmthera.2024.108773","DOIUrl":"10.1016/j.pharmthera.2024.108773","url":null,"abstract":"<div><div>The gastrointestinal tract (GIT) plays a pivotal role in the absorption of orally administered drugs, with the small intestine serving as the primary site due to its extensive surface area and specialized cell types, including enterocytes and M cells. After oral administration, drugs are generally transported <em>via</em> the portal vein to the liver, where they undergo first-pass metabolism. This process involves various enzymatic reactions, including glucuronidation, facilitated by uridine diphosphate-glucuronosyltransferase (UGT), a major phase 2 reaction in mammalian metabolism.</div><div>UGTs conjugate glucuronic acid to a wide array of endogenous and exogenous substrates, enhancing their solubility and excretion, but significantly affecting the bioavailability and therapeutic efficacy of drugs. UGT enzymes are ubiquitously distributed across tissues, prominently in the liver, but also in the GIT, kidneys, brain, and other organs where they play crucial roles in xenobiotic metabolism.</div><div>Species-specific differences in UGT expression and activity impact the selection of animal models for pharmacological studies. Various experimental models – ranging from computational simulations (<em>in silico</em>) to laboratory experiments (<em>in vitro</em>) and animal studies (<em>in vivo</em>) – are employed throughout drug discovery and development to evaluate drug metabolism, including UGT activity.</div><div>Effective strategies to counter pre-systemic metabolism are critical for improving drug bioavailability. This review explores several approaches including prodrugs, co-administration of specific molecules or use of inhibiting excipients in formulations. Strategies incorporating these excipients in nanoformulations demonstrate notable increases in drug absorption and bioavailability.</div><div>This review highlights the importance of targeted delivery systems and excipient selection in overcoming metabolic barriers, aiming to optimize drug efficacy and patient outcomes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108773"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EGFL7 is a factor involved in the regulation of various essential biological mechanisms. Endothelial cells and neurons secrete the EGFL7 protein into the extracellular matrix, where it interacts with other matrix proteins, thereby regulating several important signaling pathways. To date, extensive in vitro and in vivo studies have illuminated the central role of EGFL7 in governing major biological processes involving blood vessels and the central nervous system. Notably, EGFL7 has also emerged as a key factor in a spectrum of diseases including cancer, stroke, multiple sclerosis and preeclampsia. Its influence on various diseases and multiple regulatory pathways highlights EGFL7 as an emerging biomarker and therapeutic target. Thus, the multifaceted regulatory functions of EGFL7 will be discussed in the physiological context before delving into its involvement in the progression of different diseases. Finally, the review will provide an insight into the broad therapeutic potential of EGFL7 by describing its role as a powerful biomarker and discussing potential strategies to therapeutically target EGFL7 function in a plethora of human diseases.
{"title":"EGFL7: An emerging biomarker with great therapeutic potential","authors":"Carina Fabian , Sukrit Mahajan , Mirko H.H. Schmidt","doi":"10.1016/j.pharmthera.2024.108764","DOIUrl":"10.1016/j.pharmthera.2024.108764","url":null,"abstract":"<div><div>EGFL7 is a factor involved in the regulation of various essential biological mechanisms. Endothelial cells and neurons secrete the EGFL7 protein into the extracellular matrix, where it interacts with other matrix proteins, thereby regulating several important signaling pathways. To date, extensive <em>in vitro</em> and <em>in vivo</em> studies have illuminated the central role of EGFL7 in governing major biological processes involving blood vessels and the central nervous system. Notably, EGFL7 has also emerged as a key factor in a spectrum of diseases including cancer, stroke, multiple sclerosis and preeclampsia. Its influence on various diseases and multiple regulatory pathways highlights EGFL7 as an emerging biomarker and therapeutic target. Thus, the multifaceted regulatory functions of EGFL7 will be discussed in the physiological context before delving into its involvement in the progression of different diseases. Finally, the review will provide an insight into the broad therapeutic potential of EGFL7 by describing its role as a powerful biomarker and discussing potential strategies to therapeutically target EGFL7 function in a plethora of human diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108764"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.pharmthera.2024.108759
Milica Gajić Bojić , Jovana Aranđelović , Ranko Škrbić , Miroslav M. Savić
The role of γ- aminobutyric acid (GABA) and GABAA receptors is not only essential for neurotransmission in the central nervous system (CNS), but they are also involved in communication in various peripheral tissues such as the pancreas, liver, kidney, gastrointestinal tract, trachea, immune cells and blood vessels. GABAA receptors located outside the CNS (“peripheral GABAA receptors”) enable both neuronal and non-neuronal GABA-ergic signaling in various physiological processes and are generally thought to have similar properties to the extrasynaptic receptors in the CNS. By activating these peripheral receptors, GABA and various GABAA receptor modulators, including drugs such as benzodiazepines and general anesthetics, may contribute to or otherwise affect the maintenance of general body homeostasis. However, the existing data in the literature on the role of non-neuronal GABA-ergic signaling in insulin secretion, glucose metabolism, renal function, intestinal motility, airway tone, immune response and blood pressure regulation are far from complete. In fact, they mainly focus on the identification of components for the local synthesis and utilization of GABA and on the expression repertoire of GABAA receptor subunits rather than on subunit composition, activation effects and (sub)cellular localization. A deeper understanding of how modulation of peripheral GABAA receptors can have significant therapeutic effects on a range of pathological conditions such as multiple sclerosis, diabetes, irritable bowel syndrome, asthma or hypertension could contribute to the development of more specific pharmacological strategies that would provide an alternative or complement to existing therapies. Selective GABAA receptor modulators with improved peripheral efficacy and reduced central side effects would therefore be highly desirable first-in-class drug candidates. This review updates recent advances unraveling the molecular components and cellular determinants of the GABA signaling machinery in peripheral organs, tissues and cells of both, humans and experimental animals.
{"title":"Peripheral GABAA receptors - Physiological relevance and therapeutic implications","authors":"Milica Gajić Bojić , Jovana Aranđelović , Ranko Škrbić , Miroslav M. Savić","doi":"10.1016/j.pharmthera.2024.108759","DOIUrl":"10.1016/j.pharmthera.2024.108759","url":null,"abstract":"<div><div>The role of γ- aminobutyric acid (GABA) and GABA<sub>A</sub> receptors is not only essential for neurotransmission in the central nervous system (CNS), but they are also involved in communication in various peripheral tissues such as the pancreas, liver, kidney, gastrointestinal tract, trachea, immune cells and blood vessels. GABA<sub>A</sub> receptors located outside the CNS (“peripheral GABA<sub>A</sub> receptors”) enable both neuronal and non-neuronal GABA-ergic signaling in various physiological processes and are generally thought to have similar properties to the extrasynaptic receptors in the CNS. By activating these peripheral receptors, GABA and various GABA<sub>A</sub> receptor modulators, including drugs such as benzodiazepines and general anesthetics, may contribute to or otherwise affect the maintenance of general body homeostasis. However, the existing data in the literature on the role of non-neuronal GABA-ergic signaling in insulin secretion, glucose metabolism, renal function, intestinal motility, airway tone, immune response and blood pressure regulation are far from complete. In fact, they mainly focus on the identification of components for the local synthesis and utilization of GABA and on the expression repertoire of GABA<sub>A</sub> receptor subunits rather than on subunit composition, activation effects and (sub)cellular localization. A deeper understanding of how modulation of peripheral GABA<sub>A</sub> receptors can have significant therapeutic effects on a range of pathological conditions such as multiple sclerosis, diabetes, irritable bowel syndrome, asthma or hypertension could contribute to the development of more specific pharmacological strategies that would provide an alternative or complement to existing therapies. Selective GABA<sub>A</sub> receptor modulators with improved peripheral efficacy and reduced central side effects would therefore be highly desirable first-in-class drug candidates. This review updates recent advances unraveling the molecular components and cellular determinants of the GABA signaling machinery in peripheral organs, tissues and cells of both, humans and experimental animals.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108759"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.pharmthera.2024.108788
Li-Kun Yang , Wei Wang , Dong-Yu Guo , Bo Dong
G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the mammalian genomes, regulate almost all known physiological processes by transducing numerous extracellular stimuli including almost two-thirds of endogenous hormones and neurotransmitters. The traditional view held that GPCR signaling occurs exclusively at the cell surface, where the receptors bind with the ligands and undergo conformational changes to recruit and activate heterotrimeric G proteins. However, with the application of advanced biochemical and biophysical techniques, this conventional model is challenged by the elucidation of spatiotemporal GPCR activation with the evidence that receptors can signal from subcellular compartments to exhibit various molecular and cellular responses with physiological and pathophysiological relevance. Thus, this ‘location bias’ of GPCR signaling has become another layer of complexity of GPCR signal transduction. In this review, we generally introduce the development of the concept of compartmentalized GPCR signaling and comprehensively summarize the receptors reported to be localized on the membranes of different intracellular organelles. We review the physiological functions of these compartmentalized GPCRs with emphasis on some well-characterized prototypical hormone/neurotransmitter-binding receptors, including β2-adrenergic receptor, opioid receptors, parathyroid hormone type 1 receptor, thyroid-stimulating hormone receptor, cannabinoid receptor type 1, and metabotropic glutamate receptor 5, as examples. In addition, the therapeutic implications of compartmentalized GPCR signaling by introducing lipophilic or hydrophilic ligands for intracellular targeting, lipid conjugation anchor drugs, and strategy to modulate receptor internalization/resensitization, are highlighted and open new avenues in GPCR pharmacology and therapeutics.
{"title":"Non-canonical signaling initiated by hormone-responsive G protein-coupled receptors from subcellular compartments","authors":"Li-Kun Yang , Wei Wang , Dong-Yu Guo , Bo Dong","doi":"10.1016/j.pharmthera.2024.108788","DOIUrl":"10.1016/j.pharmthera.2024.108788","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the mammalian genomes, regulate almost all known physiological processes by transducing numerous extracellular stimuli including almost two-thirds of endogenous hormones and neurotransmitters. The traditional view held that GPCR signaling occurs exclusively at the cell surface, where the receptors bind with the ligands and undergo conformational changes to recruit and activate heterotrimeric G proteins. However, with the application of advanced biochemical and biophysical techniques, this conventional model is challenged by the elucidation of spatiotemporal GPCR activation with the evidence that receptors can signal from subcellular compartments to exhibit various molecular and cellular responses with physiological and pathophysiological relevance. Thus, this ‘location bias’ of GPCR signaling has become another layer of complexity of GPCR signal transduction. In this review, we generally introduce the development of the concept of compartmentalized GPCR signaling and comprehensively summarize the receptors reported to be localized on the membranes of different intracellular organelles. We review the physiological functions of these compartmentalized GPCRs with emphasis on some well-characterized prototypical hormone/neurotransmitter-binding receptors, including β<sub>2</sub>-adrenergic receptor, opioid receptors, parathyroid hormone type 1 receptor, thyroid-stimulating hormone receptor, cannabinoid receptor type 1, and metabotropic glutamate receptor 5, as examples. In addition, the therapeutic implications of compartmentalized GPCR signaling by introducing lipophilic or hydrophilic ligands for intracellular targeting, lipid conjugation anchor drugs, and strategy to modulate receptor internalization/resensitization, are highlighted and open new avenues in GPCR pharmacology and therapeutics.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"266 ","pages":"Article 108788"},"PeriodicalIF":12.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.pharmthera.2025.108807
Jialing Huang , Yuelin Hu , Shuqing Wang , Yuefang Liu , Xin Sun , Xin Wang , Hongsong Yu
Autoimmune diseases involve a variety of cell types, yet the intricacies of their individual roles within molecular mechanisms and therapeutic strategies remain poorly understood. Single-cell RNA sequencing (scRNA-seq) offers detailed insights into transcriptional diversity at the single-cell level, significantly advancing research in autoimmune diseases. This article explores how scRNA-seq enhances the understanding of cellular heterogeneity and its potential applications in the etiology, diagnosis, treatment, and prognosis of autoimmune diseases. By revealing a comprehensive cellular landscape, scRNA-seq illuminates the functional regulation of different cell subtypes during disease progression. It aids in identifying diagnostic and prognostic markers, and analyzing cell communication networks to uncover potential therapeutic targets. Despite its valuable contributions, addressing the limitations of scRNA-seq is essential for making further advancements.
{"title":"Single-cell RNA sequencing in autoimmune diseases: New insights and challenges","authors":"Jialing Huang , Yuelin Hu , Shuqing Wang , Yuefang Liu , Xin Sun , Xin Wang , Hongsong Yu","doi":"10.1016/j.pharmthera.2025.108807","DOIUrl":"10.1016/j.pharmthera.2025.108807","url":null,"abstract":"<div><div>Autoimmune diseases involve a variety of cell types, yet the intricacies of their individual roles within molecular mechanisms and therapeutic strategies remain poorly understood. Single-cell RNA sequencing (scRNA-seq) offers detailed insights into transcriptional diversity at the single-cell level, significantly advancing research in autoimmune diseases. This article explores how scRNA-seq enhances the understanding of cellular heterogeneity and its potential applications in the etiology, diagnosis, treatment, and prognosis of autoimmune diseases. By revealing a comprehensive cellular landscape, scRNA-seq illuminates the functional regulation of different cell subtypes during disease progression. It aids in identifying diagnostic and prognostic markers, and analyzing cell communication networks to uncover potential therapeutic targets. Despite its valuable contributions, addressing the limitations of scRNA-seq is essential for making further advancements.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108807"},"PeriodicalIF":12.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1016/j.pharmthera.2025.108801
Zixuan Wang , Junren Liu , Ying Chen , Yi Tang , Ting Chen , Chang Zhou , Shuo Wang , Ranbo Chang , Zhongshuai Chen , Wenqing Yang , Zhen Guo , Ting Chen
Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.
{"title":"From physiology to pathology: Emerging roles of GPER in cardiovascular disease","authors":"Zixuan Wang , Junren Liu , Ying Chen , Yi Tang , Ting Chen , Chang Zhou , Shuo Wang , Ranbo Chang , Zhongshuai Chen , Wenqing Yang , Zhen Guo , Ting Chen","doi":"10.1016/j.pharmthera.2025.108801","DOIUrl":"10.1016/j.pharmthera.2025.108801","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108801"},"PeriodicalIF":12.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior by forming a ligand–receptor-effector (ternary) complex that functions via allosterism. Peptides constitute an important class of ligands that interact with their cognate GPCRs (peptide-GPCRs) to form the ternary complex. “Biased agonism”, a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of signalling bias at peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.
{"title":"Biased agonism in peptide-GPCRs: A structural perspective","authors":"Tharindunee Jayakody , Dinath Kavishka Budagoda , Krishan Mendis , Withanage Dhanuka Dilshan , Duvindu Bethmage , Rashmi Dissasekara , Gavin Stewart Dawe","doi":"10.1016/j.pharmthera.2025.108806","DOIUrl":"10.1016/j.pharmthera.2025.108806","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are dynamic membrane receptors that transduce extracellular signals to the cell interior by forming a ligand–receptor-effector (ternary) complex that functions via allosterism. Peptides constitute an important class of ligands that interact with their cognate GPCRs (peptide-GPCRs) to form the ternary complex. “Biased agonism”, a therapeutically relevant phenomenon exhibited by GPCRs owing to their allosteric nature, has also been observed in peptide-GPCRs, leading to the development of selective therapeutics with fewer side effects. In this review, we have focused on the structural basis of signalling bias at peptide-GPCRs of classes A and B, and reviewed the therapeutic relevance of bias at peptide-GPCRs, with the hope of contributing to the discovery of novel biased peptide drugs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108806"},"PeriodicalIF":12.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.pharmthera.2025.108799
Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour
While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.
{"title":"Bridging the gap: The endocannabinoid system as a functional fulcrum for benzodiazepines in a novel frontier of anxiety pharmacotherapy","authors":"Sina Pakkhesal , Mohammad Shakouri , Reza Mosaddeghi-Heris , Sepideh Kiani Nasab , Negin Salehi , AmirMohammad Sharafi , Ali Ahmadalipour","doi":"10.1016/j.pharmthera.2025.108799","DOIUrl":"10.1016/j.pharmthera.2025.108799","url":null,"abstract":"<div><div>While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses. Moreover, studies have provided evidence of interactions between the eCB system and benzodiazepines in anxiety modulation. For instance, the attenuation of benzodiazepine-induced anxiolysis by cannabinoid receptor antagonism or genetic variations in the eCB system components in animal studies, have been associated with variations in benzodiazepine response and susceptibility to anxiety disorders. The combined use of cannabinoid-based medications, such as cannabinoid receptor agonists and benzodiazepine co-administration, has shown promise in augmenting anxiolytic effects and reducing benzodiazepine dosage requirements. This article aims to comprehensively review and discuss the current evidence on the involvement of the eCB system as a key modulator of benzodiazepine-related anxiolytic effects, and further, the possible mechanisms by which the region-specific eCB system-GABAergic connectivity modulates the neuro-endocrine/behavioral stress response, providing an inclusive understanding of the complex interplay between the eCB system and benzodiazepines in the context of anxiety regulation, to inform future research and clinical practice.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108799"},"PeriodicalIF":12.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.pharmthera.2025.108802
Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu
G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.
{"title":"Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors","authors":"Li Yin , Kexin Ni , Tianqi Mao , Sheng Tian , Chunxiao Liu , Jiayao Chen , Mengze Zhou , Huanqiu Li , Qinghua Hu","doi":"10.1016/j.pharmthera.2025.108802","DOIUrl":"10.1016/j.pharmthera.2025.108802","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"267 ","pages":"Article 108802"},"PeriodicalIF":12.0,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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