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Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.
Assuntos
Neoplasias , Ubiquitina Tiolesterase , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Estrutura MolecularRESUMO
RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.
Assuntos
Descoberta de Drogas , Epigênese Genética , Homeostase , RNA , RNA MensageiroRESUMO
Reperfusion is the most effective treatment for acute myocardial infarction, markedly reducing mortality and morbidity. Reperfusion however induces necrotic and apoptotic damages to cardiomyocytes, that were viable prior to reperfusion, a process called myocardial ischemia/reperfusion injury(MI/RI). Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The population-based survey assessed men have about twice the total incidence of morbidity and mortality of women, and the sex gap in morbidity tends to diminish after age 45 years. So hormone replacement therapy (HRT) is given to treat the MI/RI, and lots of studies shows that the side effect is greater for estrogen, compared with phyestrogen. In this article, we review the important pathogenesis of myocardial ischemia reperfusion injury, the prevention and limitations of HRT. And we highlight the mechanism of phyestrogens treatment the MI/RI in experiment. The aim is to provide the theoretically new way of develop the safe and effective products for the researchers.
Assuntos
Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Fitoestrógenos/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , HumanosRESUMO
The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.
Assuntos
Neoplasias , Ubiquitina Tiolesterase , Humanos , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/enzimologia , Neoplasias/patologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Ubiquitinação , Inflamação/metabolismo , Transdução de Sinais , Ubiquitina/metabolismoRESUMO
Licorice (Glycyrrhiza glabra) is a plant of the genus Glycyrrhiza in the family Fabaceae/Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.
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Histone demethylation is a kind of epigenetic modification mediated by a variety of enzymes and participates in regulating multiple physiological and pathological events. Lysine-specific demethylase 7A is a kind of α-ketoglutarate- and Fe(II)-dependent demethylase belonging to the PHF2/8 subfamily of the JmjC demethylases. KDM7A is mainly localized in the nucleus and contributes to transcriptional activation via removing mono- and di-methyl groups from the lysine residues 9 and 27 of Histone H3. Mounting studies support that KDM7A is not only necessary for normal embryonic, neural, and skeletal development, but also associated with cancer, inflammation, osteoporosis, and other diseases. Herein, the structure of KDM7A is described by comparing the similarities and differences of its amino acid sequences of KDM7A and other Histone demethylases; the functions of KDM7A in homeostasis and dyshomeostasis are summarized via documenting its content and related signaling; the currently known KDM7A-specific inhibitors and their structural relationship are listed based on their structure optimization and pharmacological activities; and the challenges and opportunities in exploring functions and developing targeted agents of KDM7A are also prospected via presenting encountered problems and potential solutions, which will provide an insight in functional exploration and drug discovery for KDM7A-related diseases.
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An electron probe microanalyzer (EPMA) was applied to analyze the element Sr and Ca microchemistry patterns in otoliths of Larimichthys polyactis in Lüsi coastal waters of Jiangsu Province, China. The results showed that Sr was heterogeneously distributed along the sagittal plane of the otoliths. The highest Sr concentration was normally found in the otolith cores while much lower concentrations were found in the remaining areas. The corresponding Sr/Ca ratios were (7.10 +/- 1.00) and (4.79 +/- 1.01) in the former and latter, respectively, which were significantly differed (P < 0.01), but low Sr/Ca ratios even as low as (3.51 +/- 0.76) were also observed in several fish. Based on the above results of otolith microchemistry, the habitat history of L. polyactis was reconstructed as that high salinity habitats seemed to be required at the stages of hatching and post-hatching development, while the reduced salinity habitats seemed to be preferable for the growth and development at the remaining stages of the life history. Furthermore, several fish in this study had likely even experienced much lower salinity habitats at the early stages.