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Pharmaceutics Aug 2022microRNAs represent promising drugs to treat and prevent several diseases, such as diabetes mellitus. microRNA delivery brings many obstacles to overcome, and one...
microRNAs represent promising drugs to treat and prevent several diseases, such as diabetes mellitus. microRNA delivery brings many obstacles to overcome, and one strategy to bypass them is the manufacturing of self-assembled microRNA protein nanoparticles. In this work, a microRNA was combined with the cell-penetrating peptide protamine, forming so-called proticles. Previous studies demonstrated a lack of microRNA dissociation from proticles. Therefore, the goal of this study was to show the success of functionalizing binary proticles with citric acid in order to reduce the binding strength between the microRNA and protamine and further enable sufficient dissociation. Thus, we outline the importance of the present protons provided by the acid in influencing colloidal stability, achieving a constant particle size, and monodispersing the particle size distribution. The use of citric acid also provoked an increase in drug loading. Against all expectations, the AFM investigations demonstrated that our nanoparticles were loose complexes mainly consisting of water, and the addition of citric acid led to a change in shape. Moreover, a successful reduction in binding affinity and nanoparticulate stability are highlighted. Low cellular toxicity and a constant cellular uptake are demonstrated, and as uptake routes, active and passive pathways are discussed.
PubMed: 36145577
DOI: 10.3390/pharmaceutics14091829 -
Translational Cancer Research Nov 2021Protamine 1 (PRM1) is specific in sperm and plays essential roles in fertilization, also a member of cancer testis antigen (CTA) family. This study aims to summarize the... (Review)
Review
OBJECTIVE
Protamine 1 (PRM1) is specific in sperm and plays essential roles in fertilization, also a member of cancer testis antigen (CTA) family. This study aims to summarize the expression and function of PRM1 in spermatogenesis, and to broaden the current knowledge and inspire future development of PRM1-based therapeutic strategies in cancer treatment and nanomedicine.
BACKGROUND
The protamine proteins, are characterized by an arginine-rich core and cysteine residues. Humans express two types of protamine: PRM1 and PRM2. The abnormal expression or proportion of PRM1 and PRM2 is known to be associated with subfertility and infertility, especially for PRM1 which is highly evolutionary conserved in mammalians and expressed in all vertebrates. Biological functions of PRM1 have been unveiled in diverse cellular processes, such as tumorigenesis, somatic cell nucleus transfer, and drug delivery systems. Moreover, PRM1 is identified as a CTA in chronic leukemia (CLL) and colorectal cancer (CRC).
METHODS
Literature was obtained using PubMed and the keywords protamine 1, PRM1, or P1, from January 1, 1980, through July 20, 2021. We also collect the additional evidence through screening references of articles identified through the PubMed searches.
CONCLUSIONS
PRM1 is well-studied in male infertility, and further researches and attempts to develop PRM1 as novel tumor marker, as well as drug delivery vector, will be of important clinical significance.
PubMed: 35116345
DOI: 10.21037/tcr-21-1582 -
MedComm Sep 2022Messenger ribonucleic acid (mRNA) vaccines made their successful public debut in the effort against the COVID-19 outbreak starting in late 2019, although the history of... (Review)
Review
Messenger ribonucleic acid (mRNA) vaccines made their successful public debut in the effort against the COVID-19 outbreak starting in late 2019, although the history of mRNA vaccines can be traced back decades. This review provides an overview to discuss the historical course and present situation of mRNA vaccine development in addition to some basic concepts that underly mRNA vaccines. We discuss the general preparation and manufacturing of mRNA vaccines and also discuss the scientific advances in the in vivo delivery system and evaluate popular approaches (i.e., lipid nanoparticle and protamine) in detail. Next, we highlight the clinical value of mRNA vaccines as potent candidates for therapeutic treatment and discuss clinical progress in the treatment of cancer and coronavirus disease 2019. Data suggest that mRNA vaccines, with several prominent advantages, have achieved encouraging results and increasing attention due to tremendous potential in disease management. Finally, we suggest some potential directions worthy of further investigation and optimization. In addition to basic research, studies that help to facilitate storage and transportation will be indispensable for practical applications.
PubMed: 36033422
DOI: 10.1002/mco2.167 -
Polymers Feb 2022Biomolecules are attractive building blocks with self-assembly ability, structural diversity, and excellent functionality for creating artificial materials. Heparin and... (Review)
Review
Biomolecules are attractive building blocks with self-assembly ability, structural diversity, and excellent functionality for creating artificial materials. Heparin and protamine, a clinically relevant pair of biomolecules used in cardiac and vascular surgery, have been shown to coassemble into particulate polyelectrolyte complexes in vitro. The resulting heparin-protamine particles exhibit adhesive properties that enable advantageous interactions with proteins, cells, and various other substances and have been employed as functional materials for biomedical applications. In this review article, we summarize recent progress in research on the use of heparin-protamine particles as drug carriers, cell adhesives, and cell labels. Studies have demonstrated that heparin-protamine particles are potentially versatile in biomedical fields from drug delivery and regenerative medicine to plastic surgery.
PubMed: 35267754
DOI: 10.3390/polym14050932 -
Acta Pharmaceutica Sinica. B Mar 2023Lipid-formulated RNA vaccines have been widely used for disease prevention and treatment, yet their mechanism of action and individual components contributing to such...
Lipid-formulated RNA vaccines have been widely used for disease prevention and treatment, yet their mechanism of action and individual components contributing to such actions remain to be delineated. Here, we show that a therapeutic cancer vaccine composed of a protamine/mRNA core and a lipid shell is highly potent in promoting cytotoxic CD8 T cell responses and mediating anti-tumor immunity. Mechanistically, both the mRNA core and lipid shell are needed to fully stimulate the expression of type I interferons and inflammatory cytokines in dendritic cells. Stimulation of interferon- expression is exclusively dependent on STING, and antitumor activity from the mRNA vaccine is significantly compromised in mice with a defective gene. Thus, the mRNA vaccine elicits STING-dependent antitumor immunity.
PubMed: 36970194
DOI: 10.1016/j.apsb.2022.11.013 -
Results and Problems in Cell... 2022Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads... (Review)
Review
Sperm nuclei present a highly organized and condensed chromatin due to the interchange of histones by protamines during spermiogenesis. This high DNA condensation leads to almost inert chromatin, with the impossibility of conducting gene transcription as in most other somatic cells. The major chromosomal structure responsible for DNA condensation is the formation of protamine-DNA toroids containing 25-50 kilobases of DNA. These toroids are connected by toroid linker regions (TLR), which attach them to the nuclear matrix, as matrix attachment regions (MAR) do in somatic cells. Despite this high degree of condensation, evidence shows that sperm chromatin contains vulnerable elements that can be degraded even in fully condensed chromatin, which may correspond to chromatin regions that transfer functionality to the zygote at fertilization. This chapter covers an updated review of our model for sperm chromatin structure and its potential functional elements that affect embryo development.
Topics: Male; Humans; Semen; Chromatin; Spermatozoa; Protamines; DNA
PubMed: 36348112
DOI: 10.1007/978-3-031-06573-6_10 -
Nature Communications May 2023Genetic studies elucidate a link between testis-specific serine/threonine kinases (TSSKs) and male infertility in mammals, but the underlying mechanisms are unclear....
Genetic studies elucidate a link between testis-specific serine/threonine kinases (TSSKs) and male infertility in mammals, but the underlying mechanisms are unclear. Here, we identify a TSSK homolog in Drosophila, CG14305 (termed dTSSK), whose mutation impairs the histone-to-protamine transition during spermiogenesis and causes multiple phenotypic defects in nuclear shaping, DNA condensation, and flagellar organization in spermatids. Genetic analysis demonstrates that kinase catalytic activity of dTSSK, which is functionally conserved with human TSSKs, is essential for male fertility. Phosphoproteomics identify 828 phosphopeptides/449 proteins as potential substrates of dTSSK enriched primarily in microtubule-based processes, flagellar organization and mobility, and spermatid differentiation and development, suggesting that dTSSK phosphorylates various proteins to orchestrate postmeiotic spermiogenesis. Among them, the two substrates, protamine-like protein Mst77F/Ser and transition protein Mst33A/Ser, are biochemically validated to be phosphorylated by dTSSK in vitro, and are genetically demonstrated to be involved in spermiogenesis in vivo. Collectively, our findings demonstrate that broad phosphorylation mediated by TSSKs plays an indispensable role in spermiogenesis.
Topics: Animals; Male; Humans; Protein Serine-Threonine Kinases; Testis; Phosphorylation; Spermatogenesis; Histones; Drosophila; Protamines; Fertility; Serine; Threonine; Mammals
PubMed: 37149634
DOI: 10.1038/s41467-023-38357-0 -
Cell Death & Disease Apr 2021Infertile ovotestis (mixture of ovary and testis) often occurs in intersex individuals under certain pathological and physiological conditions. However, how ovotestis is...
Infertile ovotestis (mixture of ovary and testis) often occurs in intersex individuals under certain pathological and physiological conditions. However, how ovotestis is formed remains largely unknown. Here, we report the first comprehensive single-cell developmental atlas of the model ovotestis. We provide an overview of cell identities and a roadmap of germline, niche, and stem cell development in ovotestis by cell lineage reconstruction and a uniform manifold approximation and projection. We identify common progenitors of germline stem cells with two states, which reveal their bipotential nature to differentiate into both spermatogonial stem cells and female germline stem cells. Moreover, we found that ovotestis infertility was caused by degradation of female germline cells via liquid-liquid phase separation of the proteasomes in the nucleus, and impaired histone-to-protamine replacement in spermatid differentiation. Notably, signaling pathways in gonadal niche cells and their interaction with germlines synergistically determined distinct cell fate of both male and female germlines. Overall, we reveal a cellular fate map of germline and niche cell development that shapes cell differentiation direction of ovotestis, and provide novel insights into ovotestis development.
Topics: Animals; Cell Differentiation; Female; Germ Cells; Male; Sexual Selection
PubMed: 33846307
DOI: 10.1038/s41419-021-03676-x -
BioRxiv : the Preprint Server For... Dec 2023In sperm cells, protamine replaces histones to compact DNA 10-20 times more than in somatic cells. To characterize the extreme compaction, we employed confocal...
In sperm cells, protamine replaces histones to compact DNA 10-20 times more than in somatic cells. To characterize the extreme compaction, we employed confocal microscopy and optical tweezers to determine the conformations and stability of protamine-bound λ-DNA. Confocal images show increasing compaction of λ-DNA at increasing protamine concentration. In the presence of protamine, single λ-DNA molecules form bends and loops that unravel at 10-40 pN forces as well as coils that shorten the contour length by up to 40% and withstand forces strong enough (~55 pN) for strand separation. Strand separation nucleates coils, indicating protamine insertion into DNA bases. Protamine may participate in both local and higher-order chromatin organization, leading to extreme compaction and global transcription silencing.
PubMed: 38106194
DOI: 10.1101/2023.12.08.570784 -
Veterinary World Mar 2020Fertility is the most important aspect in the efforts to increase livestock populations. Protamine and various proteins in sperm and seminal plasma are the results of... (Review)
Review
Fertility is the most important aspect in the efforts to increase livestock populations. Protamine and various proteins in sperm and seminal plasma are the results of the molecular analysis which can be used as a marker of fertility. Each of the proteins plays an important role in the normal function of sperm, starting from the formation of sperm structure, motility, capacitation, cell protection, acrosome reactions, successful fertilization, egg activation, and embryonic development. Finally, these molecular components can be a marker of fertility and can help to diagnose the cases of infertility/subfertility in livestock in the field.
PubMed: 32367964
DOI: 10.14202/vetworld.2020.556-562