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Ultrashort peptides (USPs), consisting of 2-7 amino-acid residues, are a group of signaling molecules that regulate gene expression and protein synthesis under normal conditions in various diseases and ageing. USPs serve as a basis for the development of drugs with a targeted mechanism of action. The purpose of this review is to systematize the ava...
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... is likely that LAT1 partially explains the mechanism of USP penetration into tissues, but to get a more thorough understanding, additional studies using molecular modeling methods are needed in order to identify the features of the USP interaction with other L and POT system carriers. Figure 2 gives a schematic representation of the short-peptide transport through carrier proteins in various tissues. Orally ingested amino acids and USPs are transported to intestinal cells, presumably by the PEPT1 transporter at the apical side of the membrane, and afterwards they enter the blood flow through the basolateral membrane via L-system transporters. ...
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... Additionally, small peptides can serve as an antioxidant by scavenging the body's excessive free radicals and regulate the activity of related antioxidant enzymes to achieve antioxidation (Liu and Zhao, 2010;Zou et al., 2016). Current studies on small peptides have mainly focused on traditional nutrition and small peptide intestinal transport carriers (Hu et al., 2010;Khavinson et al., 2022). Studies on small peptide metabolic regulation pathways at cellular and molecular levels are rare. ...
Small peptides are nutrients and bioactive molecules that have dual regulatory effects on nutrition and physiology. They are of great significance for maintaining the intestinal health and production performance of broilers. We here cultured the primary small intestinal epithelial cells (IEC) of chicken in a medium containing L-Leu (Leu) and L-Leu-L-Leu (Leu-Leu) for 24 h. The untreated cells were considered as the control group. The growth, proliferation, and apoptosis of IEC were examined. By combining RNA-seq and label-free sequencing technology, candidate genes, proteins, and pathways related to the growth, proliferation, and apoptosis of IEC were screened. Immunofluorescence detection revealed that the purity of the isolated primary IEC was >90%. The Leu-Leu group significantly promoted IEC growth and proliferation and significantly inhibited IEC apoptosis, and the effect was better than those of the Leu and control groups. Using transcriptome sequencing, four candidate genes, CCL20, IL8L1, IL8, and IL6, were screened in the Leu group, and one candidate gene, IL8, was screened in the Leu-Leu group. Two candidate genes, IL6 and RGN, were screened in the Leu-Leu group compared with the Leu group. Nonquantitative proteomic marker sequencing results revealed that through the screening of candidate proteins and pathways, found one growth-related candidate protein PGM3 and three proliferation-related candidate proteins RPS17, RPS11, and RPL23, and two apoptosis-related candidate proteins GPX4 and PDPK1 were found in the Leu-Leu group compared with Leu group. In short, Leu-Leu could promote IEC growth and proliferation and inhibit IEC apoptosis. On combining transcriptome and proteome sequencing technologies, multiple immune- and energy-related regulatory signal pathways were found to be related to IEC growth, proliferation, and apoptosis. Three candidate genes of IL8, IL6, and RGN were identified, and six candidate proteins of PGM3, RPS17, RPS11, RPL23, GPX4, and PDPK1 were involved in IEC growth, proliferation, and apoptosis. The results provide valuable data for preliminarily elucidating small peptide-mediated IEC regulation pathways, improving the small peptide nutrition theoretical system, and establishing small peptide nutrition regulation technology.
... Numerous in vitro studies on peptides have demonstrated their ability to form amyloidlike structures endowed with special mechanical and spectroscopic properties with enormous implications in the biomedical and technological area [5]. Despite the interest aroused by this phenomenon, the physical basis of its origin is still poorly understood. ...
Peptides are increasingly emerging as a drug class for a wide range of human diseases due to their intrinsic properties, such as excellent recognition abilities and biocompatibility [...]
... PEPT1, a low-affinity peptide transporter, is primarily expressed in the small intestine and is also found in low amounts in the kidneys. On the other hand, PEPT2, a high-affinity peptide transporter, is mainly expressed at the apical membrane of renal proximal tubular cells [26][27][28]. The structure of PEPTs contains multiple binding sites for binding to peptides. ...
The kidney is critical in the human body’s excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug–drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro–in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject’s situation when they are going to study DDIs mediated by renal transporters.
... As contrasted with dipeptides, tripeptides' binding characteristics to the LAT1 transporter are much higher, and therefore tripeptides appear as preferred candidates for the anticancer drug development. * Preliminary results of USP docking at the LAT1 active site are presented in a recently published review of the literature on the structure and biological activity of the LAT and POT family transporters [4]. The data obtained in this work differ somewhat from preliminary calculations due to the use of several different conformations of the LAT1 active site, which is observed in various LAT1 structures available in PDB (PDB ID: 6IRS), as well as the use of new, more advanced techniques for docking mobile ligands with increased thoroughness. ...
... −31.50 0.35 [29] 2 * Preliminary results of USP docking at the LAT1 active site are presented in a recently published review of the literature on the structure and biological activity of the LAT and POT family transporters [4]. The data obtained in this work differ somewhat from preliminary calculations due to the use of several different conformations of the LAT1 active site, which is observed in various LAT1 structures available in PDB (PDB ID: 6IRS), as well as the use of new, more advanced techniques for docking mobile ligands with increased thoroughness. ...
... Inhibitors of the neutral amino acid transporter LAT1 with known IC50 values used f L-Leu transport inhibition in Pichia pastoris cells and proteoliposomes.* Preliminary results of USP docking at the LAT1 active site are presented in a recently published review of the literature on the structure and biological activity of the LAT and POT family transporters[4]. The data obtained in this work differ somewhat from preliminary calculations due to the use of several different conformations of the LAT1 active site, which is observed in various LAT1 structures available in PDB (PDB ID: 6IRS), as well as the use of new, more advanced techniques for docking mobile ligands with increased thoroughness. ...
The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters. Molecular modeling and computer-assisted docking of peptide ligands revealed that the size and structure of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analysis of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters has been carried out. The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides, for which no biological activity has been established. This indicates an important possible role which LAT and PEPT family transporters may play in a variety of biological activities of the 26 biologically active peptides under investigation in this study. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp− or Glu− amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide are found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters. The data obtained lead to new prospects for further study of the mechanisms of transport of USP-based drugs into the cell and design of new antitumor drugs.
... Many peptides have a physiological mechanism of action and, according to their biological activity, can be classified as senomorphic substances. Short peptides consisting of two to seven amino acid residues can penetrate into the cytoplasm, nucleus, and nucleolus of the cell and interact with the nucleosome, histone proteins, and DNA [117][118][119]. ...
... Currently, the mechanism of the short peptides' transportation into the cell is only being studied. One of the hypotheses suggests the involvement of POT and LAT peptide carriers in this process [117]. However, there is already evidence of the successful use of some short peptides in clinical practice. ...
A senescence-associated secretory phenotype (SASP) and a mild inflammatory response characteristic of senescent cells (inflammaging) form the conditions for the development of cardiovascular diseases: atherosclerosis, coronary heart disease, and myocardial infarction. The purpose of the review is to analyze the pool of signaling molecules that form SASP and inflammaging in cells of the cardiovascular system and to search for targets for the action of vasoprotective peptides. The SASP of cells of the cardiovascular system is characterized by a change in the synthesis of anti-proliferative proteins (p16, p19, p21, p38, p53), cytokines characteristic of inflammaging (IL-1α,β, IL-4, IL-6, IL-8, IL-18, TNFα, TGFβ1, NF-κB, MCP), matrix metalloproteinases, adhesion molecules, and sirtuins. It has been established that peptides are physiological regulators of body functions. Vasoprotective polypeptides (liraglutide, atrial natriuretic peptide, mimetics of relaxin, Ucn1, and adropin), KED tripeptide, and AEDR tetrapeptide regulate the synthesis of molecules involved in inflammaging and SASP-forming cells of the cardiovascular system. This indicates the prospects for the development of drugs based on peptides for the treatment of age-associated cardiovascular pathology.
Human proton-coupled oligopeptide transporters (PepTs) are important membrane influx transporters that facilitate the cellular uptake of many drugs including ACE inhibitors and antibiotics. PepTs mediate the absorption of di- and tri-peptides from dietary proteins or gastrointestinal secretions, facilitate the reabsorption of peptide-bound amino acids in the kidney, and regulate neuropeptide homeostasis in extracellular fluids. PepT1 and PepT2 have been the most intensively investigated of all PepT isoforms. Modulating the interactions of PepTs and their drug substrates could influence treatment outcomes and adverse effects with certain therapies. In recent studies, topology models and protein structures of PepTs have been developed. The aim of this review was to summarise the current knowledge regarding structure-interaction relationships (SIRs) of PepTs and their substrates as well as the potential applications of this information in therapeutic optimisation and drug development. Such information may provide insights into the efficacy of PepT drug substrates in patients, mechanisms of drug–drug/food interactions and the potential role of PepTs targeting in drug design and development strategies.
