Various studies have correlated the mechanical properties of the aortic wall with its biochemical parameters and inner structure. Very few studies have addressed correlations with the cohesive properties, which are crucial for understanding fracture phenomena such as aortic dissection, i.e. a life-threatening process. Aimed at filling this gap, we conducted a comprehensive biochemical and histological analysis of human aortas (the ascending and descending thoracic and infrarenal abdominal aorta) from 34 cadavers obtained post-mortem during regular autopsies. The pentosidine, hydroxyproline and calcium contents, calcium/phosphorus molar ratio, degree of atherosclerosis, area fraction of elastin, collagen type I and III, alpha smooth muscle actin, vasa vasorum, vasa vasorum density, aortic wall thickness, thicknesses of the adventitia, media and intima were determined and correlated with the delamination forces in the longitudinal and circumferential directions of the vessel as determined from identical cadavers. The majority of the parameters determined did not indicate significant correlation with age, except for the calcium content and collagen maturation (enzymatic crosslinking). The main results concern differences between enzymatic and non-enzymatic crosslinking and those caused by the presence of atherosclerosis. The enzymatic crosslinking of collagen increased with age and was accompanied by a decrease in the delamination strength, while non-enzymatic crosslinking tended to decrease with age and was accompanied by an increase in the delamination strength. As the rate of calcification increased, the presence of atherosclerosis led to the formation of calcium phosphate plaques with higher solubility than the tissue without or with only mild signs of atherosclerosis. STATEMENT OF SIGNIFICANCE: This study presents a detailed biochemical and histological analysis of human aortic samples (ascending thoracic aorta, descending thoracic aorta and infrarenal abdominal aorta) taken from 34 cadavers. The contribution of this scientific study lies in the detailed biochemical comparison of the enzymatic and non-enzymatic glycosylation-derived crosslinks of vascular tissues and their influence on the delamination strength of the human aorta since, to the best of our knowledge, no such comprehensive studies exist in the literature. A further benefit concerns the notification of the limitations of the various analytical methods applied; an important factor that must be taken into account in such studies.
- MeSH
- Actins metabolism MeSH
- Aorta * metabolism MeSH
- Arginine analogs & derivatives MeSH
- Atherosclerosis metabolism pathology MeSH
- Adult MeSH
- Elastin metabolism MeSH
- Hydroxyproline metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Lysine analogs & derivatives metabolism MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Aging * physiology MeSH
- Calcium metabolism MeSH
- Vasa Vasorum metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Keywords
- Tislelizumab, tofersen, Danikopan,
- MeSH
- Aminopyridines pharmacology therapeutic use MeSH
- Amyotrophic Lateral Sclerosis drug therapy MeSH
- Renal Insufficiency, Chronic drug therapy MeSH
- Diabetes Mellitus drug therapy MeSH
- Insulin, Long-Acting pharmacology therapeutic use MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Oligonucleotides pharmacology therapeutic use MeSH
- Hemoglobinuria, Paroxysmal drug therapy MeSH
- Proline pharmacology therapeutic use MeSH
- Registries * MeSH
- Drug Approval * MeSH
- Check Tag
- Humans MeSH
Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.
- MeSH
- Baroreflex * drug effects MeSH
- Hypertension drug therapy physiopathology enzymology MeSH
- Angiotensin-Converting Enzyme Inhibitors * pharmacology MeSH
- Captopril * pharmacology MeSH
- Blood Pressure * drug effects MeSH
- Rats MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Heart Rate * drug effects MeSH
- Sympathetic Nervous System * drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Although many efforts have been made to improve management strategies and diagnostic methods in the past several decades, the prevention of anastomotic complications, such as anastomotic leaks and strictures, remain a major clinical challenge. Therefore, new molecular pathways need to be identified that regulate anastomotic healing, and to design new treatments for patients after anastomosis to reduce the occurrence of complications. Rabbits were treated with a MST1/2 inhibitor XMU-XP-1, a Chinese medicine formula Shenhuang plaster (SHP) or a control vehicle immediately after surgery. The anastomotic burst pressure, collagen deposition, and hydroxyproline concentration were evaluated at 3 and 7 days after the surgery, and qRT-PCR and western-blot analyses were used to characterize mRNA and protein expression levels. Both XMU-XP-1 and SHP significantly increased anastomotic burst pressure, collagen deposition, and the concentration of hydroxyproline in intestinal anastomotic tissue at postoperative day 7 (POD 7). Importantly, SHP could induce TGF-β1 expression, which activated its downstream target Smad-2 to activate the TGF-β1 signaling pathway. Moreover, SHP reduced the phosphorylation level of YAP and increased its active form, and treatment with verteporfin, a YAP-TEAD complex inhibitor, significantly suppressed the effects induced by SHP during anastomotic tissue healing. This study demonstrated that activation of the Hippo-YAP pathway enhances anastomotic healing, and that SHP enhances both the TGF-β1/Smad and YAP signaling pathways to promote rabbit anastomotic healing after surgery. These results suggest that SHP could be used to treat patients who underwent anastomosis to prevent the occurrence of anastomotic complications.
- MeSH
- Anastomosis, Surgical MeSH
- Hydroxyproline pharmacology MeSH
- Collagen pharmacology MeSH
- Rabbits MeSH
- Lagomorpha * metabolism MeSH
- Humans MeSH
- Cell Cycle Proteins metabolism pharmacology MeSH
- Signal Transduction MeSH
- Transforming Growth Factor beta * metabolism pharmacology MeSH
- Transforming Growth Factor beta1 pharmacology MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
An increase in phosphorylation of the Tau protein is associated with Alzheimer's disease (AD) progression through unclear molecular mechanisms. In general, phosphorylation modifies the interaction of intrinsically disordered proteins, such as Tau, with other proteins; however, elucidating the structural basis of this regulation mechanism remains challenging. The bridging integrator-1 gene is an AD genetic determinant whose gene product, BIN1, directly interacts with Tau. The proline-rich motif recognized within a Tau(210-240) peptide by the SH3 domain of BIN1 (BIN1 SH3) is defined as 216PTPP219, and this interaction is modulated by phosphorylation. Phosphorylation of T217 within the Tau(210-240) peptide led to a 6-fold reduction in the affinity, while single phosphorylation at either T212, T231, or S235 had no effect on the interaction. Nonetheless, combined phosphorylation of T231 and S235 led to a 3-fold reduction in the affinity, although these phosphorylations are not within the BIN1 SH3-bound region of the Tau peptide. Using nuclear magnetic resonance (NMR) spectroscopy, these phosphorylations were shown to affect the local secondary structure and dynamics of the Tau(210-240) peptide. Models of the (un)phosphorylated peptides were obtained from molecular dynamics (MD) simulation validated by experimental data and showed compaction of the phosphorylated peptide due to increased salt bridge formation. This dynamic folding might indirectly impact the BIN1 SH3 binding by a decreased accessibility of the binding site. Regulation of the binding might thus not only be due to local electrostatic or steric effects from phosphorylation but also to the modification of the conformational properties of Tau.
- MeSH
- Adaptor Proteins, Signal Transducing metabolism MeSH
- Alzheimer Disease * metabolism MeSH
- Phosphorylation MeSH
- Nuclear Proteins metabolism MeSH
- Humans MeSH
- Tumor Suppressor Proteins chemistry MeSH
- Peptides chemistry MeSH
- Proline metabolism MeSH
- tau Proteins * metabolism MeSH
- src Homology Domains MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
An important feature of orodispersible tablets (ODTs) is the convenient administration of the drugs, in some cases, faster onset of action, stability maintenance, and dose precision. This work focused on the preparation of ODTs containing mannitol-based co-processed excipients Prosolv® ODT G2, Ludiflash® and Parteck® ODT in combination with tramadol, captopril, and domperidone by direct compression. Prosolv® ODT G2 showed high energy of plastic deformation due to the content of microcrystalline cellulose. Parteck® ODT provided compact tablets due to the content of granulated mannitol. All drugs decreased tensile strength, increased friability, prolonged disintegration time, and decreased the porosity of tablets. Tablets containing Prosolv® ODT G2 with captopril, domperidone, and tramadol; and Parteck® ODT with domperidone met the requirements for ODTs production, i.e., friability ≤ 1% and disintegration time ≤ 180 s, fast wetting time, high water absorption ratio, and adequate tensile strength. The disintegration time was tested using both the pharmacopeial method and the BJKSN-13 apparatus. The results indicate the significant difference between these methods, with the disintegration time being longer when tested with the BJKSN-13 instrument.
Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2-4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC50 values in tens of μM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.
- MeSH
- Administration, Cutaneous MeSH
- Hydroxyproline metabolism MeSH
- Skin Absorption * MeSH
- Skin metabolism MeSH
- Carboxylic Acids metabolism MeSH
- Pharmaceutical Preparations metabolism MeSH
- Humans MeSH
- Organic Chemicals metabolism MeSH
- Permeability MeSH
- Proline * metabolism MeSH
- Pyrrolidinones pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Naturally occurring secondary amino acids, with proline as the main representative, contain an alpha-imino group in a cycle that is typically four-, five-, and six-membered. The unique ring structure exhibits exceptional properties-conformational rigidity, chemical stability, and specific roles in protein structure and folding. Many proline analogues have been used as valuable compounds for the study of metabolism of both prokaryotic and eukaryotic cells and for the synthesis of compounds with desired biological, pharmaceutical, or industrial properties. The D-forms of secondary amino acids play different roles in living organisms than the L-forms. They have different metabolic pathways, biological, physiological, and pharmacological effects, they can be indicators of changes and also serve as biomarkers of diseases. In the scientific literature, the number of articles examining D-amino acids in biological samples is increasing. The review summarises information on the occurrence and importance of D- and L-secondary amino acids-azetidic acid, proline, hydroxyprolines, pipecolic, nipecotic, hydroxypipecolic acids and related peptides containing these D-AAs, as well as the main analytical methods (mostly chromatographic) used for their enantiomeric determination in different matrices (biological samples, plants, food, water, and soil).
- MeSH
- Amino Acids * chemistry MeSH
- Imino Acids * chemistry MeSH
- Peptides MeSH
- Proline chemistry MeSH
- Stereoisomerism MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Genotoxic stress during DNA replication constitutes a serious threat to genome integrity and causes human diseases. Defects at different steps of DNA metabolism are known to induce replication stress, but the contribution of other aspects of cellular metabolism is less understood. We show that aminopeptidase P (APP1), a metalloprotease involved in the catabolism of peptides containing proline residues near their N-terminus, prevents replication-associated genome instability. Functional analysis of C. elegans mutants lacking APP-1 demonstrates that germ cells display replication defects including reduced proliferation, cell cycle arrest, and accumulation of mitotic DSBs. Despite these defects, app-1 mutants are competent in repairing DSBs induced by gamma irradiation, as well as SPO-11-dependent DSBs that initiate meiotic recombination. Moreover, in the absence of SPO-11, spontaneous DSBs arising in app-1 mutants are repaired as inter-homologue crossover events during meiosis, confirming that APP-1 is not required for homologous recombination. Thus, APP-1 prevents replication stress without having an apparent role in DSB repair. Depletion of APP1 (XPNPEP1) also causes DSB accumulation in mitotically-proliferating human cells, suggesting that APP1's role in genome stability is evolutionarily conserved. Our findings uncover an unexpected role for APP1 in genome stability, suggesting functional connections between aminopeptidase-mediated protein catabolism and DNA replication.
- MeSH
- Aminopeptidases genetics metabolism MeSH
- Cell Cycle MeSH
- Caenorhabditis elegans genetics metabolism MeSH
- Genomic Instability * MeSH
- Cell Proliferation MeSH
- Proline metabolism MeSH
- Caenorhabditis elegans Proteins metabolism MeSH
- DNA Replication MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 μM) than proline-derived compounds (Kd values of 15-38 μM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.
- MeSH
- Adamantane chemistry MeSH
- Insulin analogs & derivatives chemical synthesis metabolism MeSH
- Kinetics MeSH
- Rats MeSH
- Protein Structure, Quaternary MeSH
- Humans MeSH
- Proline chemistry MeSH
- Receptor, Insulin chemistry metabolism MeSH
- Molecular Dynamics Simulation MeSH
- Protein Stability MeSH
- Stereoisomerism MeSH
- Solid-Phase Synthesis Techniques MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
