Sameer Ahmed Bhat, Zahra Vasi, Ritika Adhikari, Anish Gudur, Asceal Ali, Liping Jiang, Rachel Ferguson, David Liang, Shafi Kuchay
{"title":"Ubiquitin proteasome system in immune regulation and therapeutics","authors":"Sameer Ahmed Bhat, Zahra Vasi, Ritika Adhikari, Anish Gudur, Asceal Ali, Liping Jiang, Rachel Ferguson, David Liang, Shafi Kuchay","doi":"10.1016/j.coph.2022.102310","DOIUrl":"10.1016/j.coph.2022.102310","url":null,"abstract":"<div><p><span><span><span>The ubiquitin proteasome system (UPS) is a proteolytic machinery for the degradation of protein substrates that are post-translationally conjugated with </span>ubiquitin polymers through the enzymatic action of </span>ubiquitin ligases<span>, in a process termed ubiquitylation<span>. Ubiquitylation of substrates precedes their proteolysis </span></span></span><em>via</em><span> proteasomes, a hierarchical feature of UPS. E3-ubiquitin ligases recruit protein substrates providing specificity for ubiquitylation. Innate and adaptive immune system networks are regulated by ubiquitylation and substrate degradation </span><em>via</em> E3-ligases/UPS. Deregulation of E3-ligases/UPS components in immune cells is involved in the development of lymphomas, neurodevelopmental abnormalities, and cancers. Targeting E3-ligases for therapeutic intervention provides opportunities to mitigate the unintended broad effects of 26S proteasome inhibition. Recently, bifunctional moieties such as PROTACs and molecular glues have been developed to re-purpose E3-ligases for targeted degradation of unwanted aberrant proteins, with a potential for clinical use. Here, we summarize the involvement of E3-ligases/UPS components in immune-related diseases with perspectives.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9768948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genna Braverman , S. Louis Bridges , Larry W. Moreland
{"title":"Tapering biologic DMARDs in rheumatoid arthritis","authors":"Genna Braverman , S. Louis Bridges , Larry W. Moreland","doi":"10.1016/j.coph.2022.102308","DOIUrl":"10.1016/j.coph.2022.102308","url":null,"abstract":"<div><p>With the arrival of biologics and the shift toward treat-to-target therapy, the possibility of a sustained clinical response has become an achievable goal for many patients with rheumatoid arthritis<span> (RA). Although biologics have revolutionized the treatment of RA, they are costly, potentially inconvenient, and carry risks of side effects. Whether they can or should be tapered in patients with tight disease control is a matter of clinical uncertainty. The major international rheumatology professional societies have all issued guidelines on this question, but across recommendations, consensus is lacking on how and when to consider therapy de-escalation. Recent evidence suggests that sustained remission or low disease activity is more attainable with dose reduction as opposed to outright discontinuation of biologic therapy, and certain predictors of successful taper have begun to be described. This article will (1) summarize the current evidence base for biologic tapering in RA, (2) outline real-world outcomes findings, (3) review important contextual factors relevant to therapy de-escalation, such as cost-effectiveness considerations and patient perspectives, and (4) conclude by summarizing current guidelines.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10576425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editorial overview: Introduction to the musculoskeletal section of current opinion in pharmacology","authors":"Christopher P. Cardozo, Helen Bramlett","doi":"10.1016/j.coph.2022.102306","DOIUrl":"10.1016/j.coph.2022.102306","url":null,"abstract":"","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10440685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel therapeutic avenues for kisspeptin","authors":"Jovanna Tsoutsouki , Ali Abbara , Waljit Dhillo","doi":"10.1016/j.coph.2022.102319","DOIUrl":"10.1016/j.coph.2022.102319","url":null,"abstract":"<div><p><span><span>Kisspeptin<span> is a hypothalamic neuropeptide<span> that acts via the hypothalamus to stimulate hypothalamic gonadotrophin-releasing hormone secretion and downstream gonadotrophin release. In health, kisspeptin induces normal puberty and modulates ovulation in healthy women. Hypothalamic kisspeptin expression is reduced in several functional reproductive disorders; thus, treating such conditions with kisspeptin is conceptually attractive. Recent studies have demonstrated that kisspeptin can induce a more physiological degree of </span></span></span>oocyte maturation during </span><em>in vitro</em><span><span> fertilisation treatment that can reduce the risk of potentially life-threatening complications such as ovarian hyperstimulation syndrome<span><span> seen with human chorionic gonadotrophin. Furthermore, chronic use of kisspeptin could potentially restore reproductive health in females with </span>hypothalamic amenorrhoea, treat hyposexual drive disorder in otherwise healthy males and has potential indications in </span></span>polycystic ovary syndrome<span><span>, osteoporosis and metabolic dysfunction-associated fatty liver disease. Finally, kisspeptin analogues could potentially overcome some of the pharmacological challenges associated with the natural forms of kisspeptin such as short duration of action and development of </span>tachyphylaxis.</span></span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10576953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laetitia Coassolo , Niels Banhos Dannieskiold-Samsøe , Meng Zhao , Hobson Allen , Katrin J. Svensson
{"title":"New players of the adipose secretome: Therapeutic opportunities and challenges","authors":"Laetitia Coassolo , Niels Banhos Dannieskiold-Samsøe , Meng Zhao , Hobson Allen , Katrin J. Svensson","doi":"10.1016/j.coph.2022.102302","DOIUrl":"10.1016/j.coph.2022.102302","url":null,"abstract":"<div><p>Adipose tissue is a functional endocrine organ comprised of adipocytes and other cell types that are known to secrete a multiplicity of adipose-derived factors, including lipids and proteins. It is well established that adipose tissue and its secretome can impact systemic energy homeostasis. The endocrine and paracrine effects of adipose-derived factors have been widely studied over the last several decades. Owing to technological advances in genomics and proteomics, several additional adipose-derived protein factors have recently been identified. By learning from previous efforts, the next challenge will be to leverage these discoveries for the prevention or treatment of metabolic disorders. Here, we discuss recently discovered adipose-derived proteins secreted from white or brown adipose tissue and the opportunities and challenges of translating these biological findings into disease therapeutics.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RAD51 paralogs: Expanding roles in replication stress responses and repair","authors":"Debanjali Bhattacharya , Satyaranjan Sahoo , Tarun Nagraj , Suruchi Dixit , Harsh Kumar Dwivedi, Ganesh Nagaraju","doi":"10.1016/j.coph.2022.102313","DOIUrl":"10.1016/j.coph.2022.102313","url":null,"abstract":"<div><p>Mammalian RAD51 paralogs are essential for cell survival and are critical for RAD51-mediated repair of DNA double-strand breaks (DSBs) by homologous recombination<span> (HR). However, the molecular mechanism by which RAD51 paralogs participate in HR is largely unclear. Germline mutations in RAD51 paralogs are associated with breast and ovarian cancers and Fanconi anemia-like disorder, underscoring the crucial roles of RAD51 paralogs in genome maintenance and tumor suppression. Despite their discovery over three decades ago, the essential functions of RAD51 paralogs in cell survival and genome stability remain obscure. Recent studies unravel DSB repair independent functions of RAD51 paralogs in replication stress responses. Here, we highlight the recent findings that uncovered the novel functions of RAD51 paralogs in replication fork progression, its stability, and restart and discuss RAD51 paralogs as a potential therapeutic target for cancer treatment.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9122328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maggie C. Evans, Rebecca E. Campbell, Greg M. Anderson
{"title":"Physiological regulation of leptin as an integrative signal of reproductive readiness","authors":"Maggie C. Evans, Rebecca E. Campbell, Greg M. Anderson","doi":"10.1016/j.coph.2022.102321","DOIUrl":"10.1016/j.coph.2022.102321","url":null,"abstract":"<div><p>Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10565699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PRRT for higher-grade neuroendocrine neoplasms: What is still acceptable?","authors":"Grace Kong , Rodney J. Hicks","doi":"10.1016/j.coph.2022.102293","DOIUrl":"10.1016/j.coph.2022.102293","url":null,"abstract":"<div><p>Peptide receptor radionuclide<span><span> therapy (PRRT) is a widely accepted treatment for progressive grade 1 and 2 (G1-2) gastroenteropancreatic neuroendocrine tumors (NET). There is increasing evidence that PRRT is effective for selected patients with well-differentiated (WD) G3 </span>NET<span>, which are now separated from neuroendocrine carcinoma<span> (NEC). These preliminary data have led to prospective PRRT trials currently in progress. This article provides an update of the current role of PRRT for patients with WD-G3 NET, highlighting the importance of patient selection based on molecular imaging phenotype, as well as outlining some potential future directions in this field. Upcoming prospective trials will help define the role, sequencing, and optimization of PRRT to improve outcomes of patients with WD-G3 NET.</span></span></span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Remyelinating strategies: What can be learned from normal brain development","authors":"John Shelestak, Muhammad Irfan, Tara M. DeSilva","doi":"10.1016/j.coph.2022.102290","DOIUrl":"10.1016/j.coph.2022.102290","url":null,"abstract":"<div><p>Multiple sclerosis (MS) is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Immunomodulatory therapies are effective in reducing relapses, however, there is no remedy for progressive disease emphasizing the need for regenerative strategies. Chronic demyelination causes axonal injury and loss which is a key component of neurodegeneration and permanent disability in MS. New oligodendrocyte progenitor cells (OPCs) proliferate in response to inflammatory demyelination representing the potential for remyelination to protect axons and preserve neuronal function. The majority of remyelinating therapies have targeted intrinsic signaling processes in oligodendrocytes to promote differentiation or utilized methods for transplantation of oligodendrocytes. Here, we discuss specific roles of microglia in contributing to normal myelin development and the significance of these functions for remyelinating strategies.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489222001175/pdfft?md5=2a165e8f21066f44addc59915856d05f&pid=1-s2.0-S1471489222001175-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10626308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}