{"title":"TRPC3: how current mechanistic understanding provides a basis for therapeutic targeting.","authors":"Klaus Groschner","doi":"10.1080/14728222.2024.2430520","DOIUrl":"10.1080/14728222.2024.2430520","url":null,"abstract":"<p><strong>Introduction: </strong>Intensive and detailed investigations of the molecular function and cellular role of mammalian transient receptor potential canonical (TRPC) channels started back in the early 90<sup>th</sup> of the past century. Initial TRPC research was fueled by high hopes to resolve fundamental questions of cellular Ca<sup>2+</sup> signaling. To date, we have learned important lessons in TRPC channel biology and biophysics, while little progress has been made in terms of therapeutic concepts.</p><p><strong>Areas covered: </strong>This is a critical account of recent progress in building a solid mechanistic basis for therapeutic interventions utilizing TRPC3 as a target. I focus on hurdles and key issues to be resolved, thereby drafting a list of essential scientific 'to-dos' on the way toward drugging of TRPC3.</p><p><strong>Expert opinion: </strong>Recent advances in the molecular physiology of TRPC3 include unveiling its lipid sensing machinery and the channels´ ability to serve spatiotemporally diverse Ca<sup>2+</sup> signaling in a cell type- and context-dependent manner. The ongoing development of technology for high-precision manipulation of the channel opens up a view on novel therapeutic strategies. It is now to unravel the complex role of TRPC3 in human physiopathology, to pinpoint the channels´ therapeutic relevance, and to further refine technologies for targeted interventions.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-9"},"PeriodicalIF":4.6,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vincent Lok, Sy Olson-McPeek, Grace Spiegelhoff, Jaqueline Cortez, David Detz, Brian Czerniecki
{"title":"Immunotherapies in breast cancer: harnessing the cancer immunity cycle.","authors":"Vincent Lok, Sy Olson-McPeek, Grace Spiegelhoff, Jaqueline Cortez, David Detz, Brian Czerniecki","doi":"10.1080/14728222.2024.2427038","DOIUrl":"https://doi.org/10.1080/14728222.2024.2427038","url":null,"abstract":"<p><strong>Introduction: </strong>Immunotherapies have found limited success in breast cancerdue to significant challenges within the tumor that block T-cell activity and function.</p><p><strong>Areas covered: </strong>The current review discusses clinically relevant immunotherapeutics and trials within the framework of the cancer-immunity cycle.</p><p><strong>Expert opinion: </strong>Current therapies such as antibody-drug conjugates and immune checkpoint blockade require proper biomarker selection, such as PD1 expression and the degree of tumor-infiltrating lymphocyte (TIL) infiltration to subset potential responders. HER2 and other tumor-associated antigens have served as valuable benchmarks for developing novel therapies, such as antibody engagers and CAR T-cells. However, further research is essential to identify and validate new target antigens that can enhance therapeutic efficacy and broaden the clinical applicability of these approaches.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-11"},"PeriodicalIF":4.6,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeted therapeutic strategies for the kidney.","authors":"Fei Yuan, Lilach O Lerman","doi":"10.1080/14728222.2024.2421756","DOIUrl":"https://doi.org/10.1080/14728222.2024.2421756","url":null,"abstract":"<p><strong>Introduction: </strong>Kidney diseases impose a significant burden with high incidence and mortality rates. Current treatment options for kidney diseases are limited, necessitating urgent development of novel and effective therapeutic strategies to delay or reverse disease progression. Targeted therapies for the kidney hold promise in significantly enhancing treatment outcomes, offering hope to patients afflicted with renal disorders.</p><p><strong>Areas covered: </strong>This review summarized advances in kidney-targeted therapies including genes, peptides and proteins, cell-based, nanoparticles, and localized delivery routes. We also explored the potential clinical applications, prospects, and challenges of targeted therapies for renal disorders.</p><p><strong>Expert opinion: </strong>Advances in targeted therapies for renal conditions have enhanced therapeutic outcomes. Clinical application of kidney-targeted therapies is currently limited by renal structure and the scarcity of robust biomarkers. Bridging the gap from basic and pre-clinical research targeting the kidney to achieving clinical translation remains a formidable challenge.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-11"},"PeriodicalIF":4.6,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wen Ma, Tingyuan Zhou, Songling Tang, Lu Gan, Yu Cao
{"title":"Advantages and disadvantages of targeting senescent endothelial cells in cardiovascular and cerebrovascular diseases based on small extracellular vesicles.","authors":"Wen Ma, Tingyuan Zhou, Songling Tang, Lu Gan, Yu Cao","doi":"10.1080/14728222.2024.2421760","DOIUrl":"https://doi.org/10.1080/14728222.2024.2421760","url":null,"abstract":"<p><strong>Introduction: </strong>With the growth of the aging population, age-related diseases have become a heavy global burden, particularly cardiovascular and cerebrovascular diseases (CVDs). Endothelial cell (EC) senescence constitutes an essential factor in the development of CVDs, prompting increased focus on strategies to alleviate or reverse EC senescence.</p><p><strong>Areas covered: </strong>Small extracellular vesicles (sEVs) are cell-derived membrane structures, that contain proteins, lipids, RNAs, metabolites, growth factors and cytokines. They are widely used in treating CVDs, and show remarkable therapeutic potential in alleviating age-related CVDs by inhibiting or reversing EC senescence. However, unclear anti-senescence mechanism poses challenges for clinical application of sEVs, and a systematic review is lacking.</p><p><strong>Expert opinion: </strong>Targeting senescent ECs with sEVs in age-related CVDs treatment represents a promising therapeutic strategy, with modifying sEVs and their contents emerging as a prevalent approach. Nevertheless, challenges remain, such as identifying and selectively targeting senescent cells, understanding the consequences of removing senescent ECs and senescence-associated secretory phenotype (SASP), and assessing the side effects of therapeutic sEVs on CVDs. More substantial experimental and clinical data are needed to advance clinical practice.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-15"},"PeriodicalIF":4.6,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potential molecular targets for the pharmacologic management of non-traumatic osteonecrosis.","authors":"Edward Y Cheng, Alireza Mirzaei","doi":"10.1080/14728222.2024.2421755","DOIUrl":"10.1080/14728222.2024.2421755","url":null,"abstract":"<p><strong>Introduction: </strong>Non-traumatic osteonecrosis is a debilitating condition marked by bone death, primarily due to reduced blood supply. Currently, no effective pharmacologic intervention is available to manage this condition effectively.</p><p><strong>Areas covered: </strong>Lipid metabolic disorders, chronic inflammation, vascular dysfunction, coagulopathy, and impaired bone homeostasis are suggested as the key pathogenic mechanisms involved in the development of non-traumatic osteonecrosis. Targeting any of these dysfunctions offers a potential avenue for pharmacologic intervention. However, the potential molecular targets for pharmacologic treatment of non-traumatic osteonecrosis remain underexplored. In this study, we reviewed available databases to compile a comprehensive set of pathogenic mechanisms and corresponding therapeutic targets for non-traumatic osteonecrosis.</p><p><strong>Expert opinion: </strong>Evidence suggests that a single pathogenic mechanism cannot fully explain the development of osteonecrosis, supporting the adoption of a multi-pathogenic theory. This theory implies that effective management of non-traumatic osteonecrosis requires targeting multiple pathogenic mechanisms simultaneously. Moreover, the same pathogenic mechanisms are unlikely to explain osteonecrosis development in patients with different etiologies. Consequently, a one-size-fits-all approach to medication is unlikely to be effective across all types of non-traumatic osteonecrosis. Future research should, therefore, focus on developing multi-target pharmacologic treatments tailored to the specific etiology of non-traumatic osteonecrosis.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"1-10"},"PeriodicalIF":4.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Zhazykbayeva, H Budde, M Kaçmaz, Y Zemedie, H Osman, R Hassoun, K Jaquet, I Akin, I El-Battrawy, M Herwig, N Hamdani
{"title":"Exploring PKG signaling as a therapeutic avenue for pressure overload, ischemia, and HFpEF.","authors":"S Zhazykbayeva, H Budde, M Kaçmaz, Y Zemedie, H Osman, R Hassoun, K Jaquet, I Akin, I El-Battrawy, M Herwig, N Hamdani","doi":"10.1080/14728222.2024.2400093","DOIUrl":"10.1080/14728222.2024.2400093","url":null,"abstract":"<p><strong>Introduction: </strong>Heart failure (HF) is a complex and heterogeneous syndrome resulting from any diastolic or systolic dysfunction of the cardiac muscle. In addition to comorbid conditions, pressure overload, and myocardial ischemia are associated with cardiac remodeling which manifests as extracellular matrix (ECM) perturbations, impaired cellular responses, and subsequent ventricular dysfunction.</p><p><strong>Areas covered: </strong>The current review discusses the main aspects of the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway (cGMP-PKG) pathway modulators and highlights the promising outcomes of its novel pharmacological boosters.</p><p><strong>Expert opinion: </strong>Among several signaling pathways involved in the pathogenesis of pressure overload, ischemia and HF with preserved ejection fraction (HFpEF) is cGMP-PKG pathway. This pathway plays a pivotal role in the regulation of cardiac contractility, and modulation of cGMP-PKG signaling, contributing to the development of the diseases. Ventricular cardiomyocytes of HF patients and animal models are known to exhibit reduced cGMP levels and disturbed cGMP signaling including hypophosphorylation of PKG downstream targets. However, restoration of cGMP-PKG signaling improves cardiomyocyte function and promotes cardioprotective effects.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"857-873"},"PeriodicalIF":5.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glykeria N Daneva, Panagiotis Tsiakanikas, Panagiotis G Adamopoulos, Andreas Scorilas
{"title":"Kallikrein-related peptidases: mechanistic understanding for potential therapeutic targeting in cancer.","authors":"Glykeria N Daneva, Panagiotis Tsiakanikas, Panagiotis G Adamopoulos, Andreas Scorilas","doi":"10.1080/14728222.2024.2415014","DOIUrl":"10.1080/14728222.2024.2415014","url":null,"abstract":"<p><strong>Introduction: </strong>Human kallikrein-related peptidases (KLKs) represent a subgroup of 15 serine endopeptidases involved in various physiological processes and pathologies, including cancer.</p><p><strong>Areas covered: </strong>This review aims to provide a comprehensive overview of the KLK family, highlighting their genomic structure, expression profiles and substrate specificity. We explore the role of KLKs in tumorigenesis, emphasizing their potential as biomarkers and therapeutic targets in cancer treatment. The dysregulated activity of KLKs has been linked to various malignancies, making them promising candidates for cancer diagnostics and therapy.</p><p><strong>Expert opinion: </strong>: Recent advancements in understanding the mechanistic pathways of KLK-related tumorigenesis offer new prospects for developing targeted cancer treatments. Expert opinion suggests that while significant progress has been made, further research is necessary to fully exploit KLKs' potential in clinical applications.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"875-894"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ULK1 as a therapeutic target in kidney diseases: Current perspective.","authors":"Shruti Shreya, Neha Dagar, Vishwadeep Shelke, Bhupendra Puri, Anil Bhanudas Gaikwad","doi":"10.1080/14728222.2024.2421762","DOIUrl":"10.1080/14728222.2024.2421762","url":null,"abstract":"<p><strong>Introduction: </strong>Globally, ~850 million people are affected by different kidney diseases. The pathogenesis of kidney diseases is intricate, where autophagy is crucial for maintaining kidney homeostasis. Iteliminates damaged organelles, thus reducing renal lesions and allowing tissue regeneration. Therefore, targeting various autophagy proteins, e.g. Unc-51-like autophagy-activating kinase 1 (ULK1), is emerging as potential therapeutic strategy against kidney disease.</p><p><strong>Areas covered: </strong>This review provides insights into the role of ULK1 as a therapeutic target in kidney diseases. Additionally, we have discussed the recent evidence based on pre-clinical studies for possible novel therapies modulating ULK1-mediated autophagy in kidney diseases.</p><p><strong>Expert opinion: </strong>ULK1 is one of the critical regulators of autophagy. Moreover, ULK1 works differently for different types of kidney disease. Considering its significant role in kidney disease pathogenesis, it could be a potential target to tackle kidney diseases. However, the dynamic molecular understanding of ULK1 in the context of various kidney diseases is still in its infancy and should be investigated further.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"911-922"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Target potential of miRNAs in ulcerative colitis: what do we know?","authors":"Peeyush Kumar, Saurabh Kedia, Vineet Ahuja","doi":"10.1080/14728222.2024.2408423","DOIUrl":"10.1080/14728222.2024.2408423","url":null,"abstract":"<p><strong>Introduction: </strong>The global rise in ulcerative colitis (UC) incidence highlights the urgent need for enhanced diagnostic and therapeutic strategies. Recent advances in genome-wide association studies (GWAS) have identified genetic loci associated with UC, providing insights into the disease's molecular mechanisms, including immune modulation, mucosal defense, and epithelial barrier function. Despite these findings, many GWAS signals are located in non-coding regions and are linked to low risk, suggesting that protein-coding genes alone do not fully explain UC's pathophysiology. Emerging research emphasizes the potential of microRNAs (miRNAs) as biomarkers and therapeutic targets due to their crucial role in UC. This review explores the current understanding of miRNAs in UC, including their mechanisms of action and their potential as both biomarkers and therapeutic targets. The present review provides the latest update on their potential as a biomarker and therapeutic target.</p><p><strong>Areas covered: </strong>This review synthesizes an extensive literature search on miRNAs in UC, focusing on their roles in the mucosal barrier, innate and adaptive immunity, and their potential applications as biomarkers and therapeutic modalities.</p><p><strong>Expert opinion: </strong>While miRNAs present promising opportunities as biomarkers and novel therapeutic agents in UC, challenges in validation, specificity, delivery, and clinical application need to be addressed through rigorous, large-scale studies.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"829-841"},"PeriodicalIF":5.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}