ABSTRACT
The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.
Subject(s)
Analgesics , Anticonvulsants , Caffeic Acids , Cinnamates , Seizures , Animals , Analgesics/pharmacology , Analgesics/chemistry , Analgesics/chemical synthesis , Anticonvulsants/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/chemical synthesis , Mice , Male , Seizures/drug therapy , Cinnamates/pharmacology , Cinnamates/chemistry , Cinnamates/chemical synthesis , Cinnamates/therapeutic use , Caffeic Acids/pharmacology , Caffeic Acids/chemistry , Caffeic Acids/therapeutic use , Caffeic Acids/chemical synthesis , Peptides/pharmacology , Peptides/chemistry , Peptides/chemical synthesis , Peptides/therapeutic use , Molecular Docking Simulation , IsomerismABSTRACT
The discovery of new peptides and their derivatives is an outcome of ongoing efforts to identify a peptide with significant biological activity for effective usage as a possible therapeutic agent. Spinorphin peptides have been documented to exhibit numerous applications and features. In this study, biologically active peptide derivatives based on novel peptide analogues of spinorphin conjugated with 5,5'-dimethyl (Dm) and 5,5'-diphenyl (Ph) hydantoin derivatives have been successfully synthesized and characterized. Scanning electron microscopy (SEM) and spectral methods such as UV-Vis, FT-IR (Fourier Transform Infrared Spectroscopy), CD (Circular Dichroism), and fluorimetry were used to characterize the microstructure of the resulting compounds. The results revealed changes in peptide morphology as a result of the restructuring of the aminoacidic sequences and aromatic bonds, which is related to the formation of intermolecular hydrogen bonds between tyrosyl groups and the hydantoin moiety. Electrochemical and fluorescence approaches were used to determine some physicochemical parameters related to the biological behavior of the compounds. The biological properties of the spinorphin derivatives were evaluated in vivo for anticonvulsant activity against the psychomotor seizures at different doses of the studied peptides. Both spinorphin analog peptides with Ph and Dm groups showed activity against all three phases of the seizure in the intravenous Pentylenetetrazole Seizure (ivPTZ) test. This suggests that hydantoin residues do not play a crucial role in the structure of spinorphin compounds and in determining the potency to raise the seizure threshold. On the other hand, analogs with a phenytoin residue are active against the drug-resistant epilepsy test (6-Hz test). In addition, bioactivity analyses revealed that the new peptide analogues have the potential to be used as antimicrobial and antioxidant compounds. These findings suggest promising avenues for further research that may lead to the development of alternative medicines or applications in various fields beyond epilepsy treatment.
ABSTRACT
Some new hemorphin-4 analogs with structures of Xxx-Pro-Trp-Thr-NH2 and Tyr-Yyy-Trp-Thr-NH2, where Xxx is 2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid or 2-amino-3-(4-dibenzylamino-2,6-dimethylphenyl)propanoic acid, and Yyy is (2S,4S)-4-amino-pyrrolidine-2-carboxylic acid, were synthesized and characterized by electrochemical and spectral analyses. In vivo anticonvulsant and antinociceptive activities of peptide derivatives were studied after intracerebroventricular injection in mice. The therapeutic effects of the modified peptides on seizures and pain in mice were evaluated to provide valuable insights into the potential applications of the novel compounds. Electrochemical characterization showed that the compounds behave as weak protolytes and that they are in a soluble, stable molecular form at physiological pH values. The antioxidant activity of the peptides was evaluated with voltammetric analyses, which were confirmed by applying the 2,2-Diphenyl-1-picrylhydrazyl method. The compounds showed satisfactory results regarding their structural stability, reaching the desired centers for the manifestation of biological activity without hydrolysis processes at 37°C and physiological pH. Dm-H4 and H4-P1 exhibited 100% and 83% potency to suppress the psychomotor seizures in the 6-Hz test compared to 67% activity of H4. Notably, only the H4-P1 had efficacy in blocking the tonic component in the maximal electroshock test with a potency comparable to H4. All investigated peptides containing unnatural conformationally restricted amino acids showed antinociceptive effects. The analogs Db-H4 and H4-P1 showed the most pronounced and long-lasting effect in both experimental models of pain induced by thermal and chemical stimuli. Dm-H4 produced a dose-dependent thermal antinociception and H4-P2 inhibited only formalin-induced pain behavior.
Subject(s)
Seizures , Animals , Mice , Male , Seizures/drug therapy , Structure-Activity Relationship , Anticonvulsants/pharmacology , Anticonvulsants/chemical synthesis , Anticonvulsants/chemistry , Pain/drug therapy , Amino Acids/chemistry , Amino Acids/pharmacology , Amino Acids/chemical synthesis , Antioxidants/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Analgesics/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Dose-Response Relationship, Drug , Disease Models, Animal , Opioid Peptides/pharmacology , Opioid Peptides/chemical synthesis , Opioid Peptides/chemistry , Analgesics, Opioid/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistryABSTRACT
Mammalian energy homeostasis is primarilly regulated by the hypothalamus and hindbrain, with the hippocampus, midbrain nuclei, and other regions implicated by evidence from human genetics studies. To understand how these non-canonical brain regions respond to imbalances in energy homeostasis, we performed two experiments examining the effects of different diets in male C57BL6 mice. In our first study, groups of six pair-housed mice were given access to chow, high-fat diet or fasted for 16 hours. In our subsequent study, two groups of 10 mice were single-housed and given access to chow or fasted for 24 h. We recorded food intake for each cage, the change in body weight for each animal, and collected hypothalamus, hippocampus, superior colliculus, inferior colliculus, frontal cortex, and zona incerta-centric samples. We performed bulk RNA sequencing on 185 samples and validated them by a series of quality control assessments including alignment quality and gene expression profiling. We believe these studies capture the transcriptomic effects of acute fasting and high-fat diet in the rodent brain and provide a valuable reference.
Subject(s)
Fasting , Obesity , RNA-Seq , Animals , Male , Mice , Brain , Diet , Mice, Inbred C57BL , Obesity/geneticsABSTRACT
Based on the pharmacophore model of opioid receptors, our team recently synthesized a series of short-chain hemorphin peptide analogs containing non-natural amino acids. They demonstrated anticonvulsant and antinociceptive activity with low neurotoxicity. In the present study, a series of novel bioconjugates of N-modified hemorphin analogs containing second pharmacophore cinnamic acids (CA) or caffeic (KA) were synthesized by a traditional solid-phase Fmoc chemistry method for peptide synthesis. Electrochemical and fluorimetric analysis, in vivo anticonvulsant and antinociceptive activity in mice were conducted on the compounds. The three CA acid- (H4-CA, H5-CA, and H7-CA) and three KA acid- (H4-KA, H5-KA, and H7-KA) conjugated hemorphin derivatives exhibited potency at the highest doses of 2 µg/5 µl, administered by intracerebroventricular (icv) mode, against seizure spread in the maximal electroshock test (MES) in mice. The KA-conjugated H5-KA derivate, at the lowest dose, was the only compound that suppressed clonic seizures in the subcutaneous pentylenetetrazol (scPTZ) test. Except for the H5-CA, all tested CA acid- and KA acid-conjugated peptide derivates had the potency to increase the latency for clonic seizures in a dose-dependent mode. The activity against the psychomotor seizures in the 6-Hz test was detected only for the H4-CA (0.5 µg) and H4-KA (0.5 µg and 1 µg), respectively. All investigated peptides showed a more pronounced antinociceptive effect in the "intraplantar formalin" test compared to the "hot plate" test. Shorter chain analogs showed a better antinociceptive profile against tonic pain. The data suggest a DOR and KOR-mediated mechanism of action. According to the docking analysis, H7-CA showed a different antinociceptive profile than other investigated peptides. The novel peptide derivates did not exhibit neurotoxicity in the rotarod test. Our findings suggest that conjugated CA and KA morphine peptides can be used to develop novel morphine-related analogs with anticonvulsant and antinociceptive activity.
Subject(s)
Anticonvulsants , Cinnamates , Seizures , Mice , Animals , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Anticonvulsants/chemistry , Molecular Docking Simulation , Seizures/chemically induced , Seizures/drug therapy , Seizures/metabolism , Pentylenetetrazole , Analgesics/pharmacology , Analgesics/therapeutic use , Analgesics/chemistry , Electroshock , Peptides/therapeutic use , Morphine Derivatives/therapeutic useABSTRACT
Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (SB1-SB4) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives SB1-Ph, SB2-Ph, SB3-Ph, and SB4-Ph, containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The SB2-Ph exhibited the highest potency to suppress the seizure spread with ED50 = 8.29 mg/kg, comparable to phenytoin (ED50 = 5.96 mg/kg). While SB2-Ph did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED50 by more than 2× and raised the protective index by more than 7× (phenytoin+SB2-Ph). The strongest correlation between in-vivo and docking study results was found for ligands' interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.
ABSTRACT
Recently, the four 5,5'-diphenylhydantoin Schiff bases, possessing different aromatic species (SB1-Ph, SB2-Ph, SB3-Ph and SB4-Ph) were synthesized, characterized, and evaluated for anticonvulsant activity in combination with phenytoin. In the present study, the SB1-Ph and SB4-Ph compounds were selected, based on their anticonvulsant potency, and compared with their cis isomers, prepared after a one-hour exposure to the UV source, for their anticonvulsant potency in the maximal electroshock (MES) test and the kainate (KA)-induced status epilepticus (SE) test in mice. In the MES test, the cisSB1-Ph compound exhibited superior to phenytoin and trans isomer activity in the three tested doses, while the cisSB4-Ph compound entirely suppressed the electroshock-induced seizure spread at the highest dose of 40 mg/kg. Pretreatment with the cisSB1-Ph compound and the cisSB4-Ph at the doses of 40 mg/kg, respectively, for seven days, significantly attenuated the severity of KA SE compared to the matched control group pretreated with a vehicle, while phenytoin was ineffective in this test. The cisSB4-Ph but not the cisSB1-Ph demonstrated an antioxidant effect against the KA-induced SE in the hippocampus. Our results suggest that trans-cis conversion of 5,5'-diphenylhydantoin Schiff bases has potential against seizure spread in the MES test and mitigated the KA-induced SE. The antioxidant potency of cisSB4-Ph might be associated with its efficacy in mitigating the SE.
Subject(s)
Anticonvulsants , Status Epilepticus , Mice , Animals , Anticonvulsants/therapeutic use , Phenytoin/pharmacology , Schiff Bases/pharmacology , Seizures/drug therapy , Seizures/chemically induced , Status Epilepticus/drug therapy , Kainic Acid/adverse effects , Electroshock/methodsABSTRACT
Valorphin (V1) is a naturally occurring peptide derived from hemoglobin that has been found to have an affinity for opioid receptors and exhibits antinociceptive and anticonvulsant activity. Some of its synthetic analogs containing an aminophosphonate moiety show structure-dependent potent antinociceptive effects. This study aimed to reveal a detailed picture of the antinociceptive mechanisms and behavioral effects of V1 and its recently synthesized phosphopeptide analog V2p in rodents using a range of methods. The studied peptides significantly reduced acute (mean V1-9.0, V2p-5.8 vs. controls-54.1 s) and inflammatory (mean V1-57.9 and V2p-53.3 vs. controls-107.6 s) nociceptive pain in the formalin test, as well as carrageenan-induced hyperalgesia (mean V1-184.7 and V2p-107.3 vs. controls-61.8 g) in the paw pressure test. These effects are mediated by activation of opioid receptors with a predominance of kappa in V1 antinociception and by delta, kappa, and mu receptors in V2p-induced antinociception. Both peptides did not change the levels of TNF-alpha and IL-1-beta in blood serum. V1 induces depression-like behavior, and V2p shows a tendency toward anxiolysis and short-term impairment of motor coordination without affecting exploratory behavior. The results characterize valorphin and its derivative as promising analgesics that exert their effects both centrally and peripherally, without causing severe behavioral changes in experimental animals. These encouraging data are a foundation for future studies focusing on the effects of hemorphins after long-term treatment.
ABSTRACT
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Subject(s)
Diabetes Mellitus, Type 2 , Glucose , Humans , Genome-Wide Association Study , Blood Glucose/genetics , Diabetes Mellitus, Type 2/genetics , ColonABSTRACT
Two series of new VV-hemorphin-5 analogs with structures Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 and Adam-Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH2 , where Xxx is Ac5c (1-aminocyclopentane-1-carboxylic acid), Ac6c (1-aminocyclohexane-1-carboxylic acid), Ac7c (1-aminocycloheptane-1-carboxylic acid), and Adam is the low-molecular-weight lipophilic adamantyl building block, were synthesized, characterized electrochemically and evaluated for antioxidant, anti-hyperalgesia, and anticonvulsant activity. The design of the compounds followed the strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme. The partition coefficient value shows that the peptide scaffold goes from hydrophilic to lipophilic with the increasing size of the cycloalkane ring and even more with the introduction of the adamantane. The peptides C5-V and C7-V were the only analogs that provoked an immediate antinociceptive effect changing the mechanical pain threshold. The six new peptide analogs produced a significant and long-lasting carrageenan model of inflammatory pain in rats. While the adamantane hemorphin analog Ad7-V was the only compound with the potency to suppress psychomotor seizures in the 6-Hz test, the C6-V and Ad6-V exhibited protective activity against the seizure spread in the maximal electroshock seizure test in mice. The active analogs did not show neurotoxicity or sedative effects. Our results revealed a structure-related specific activity of a newly designed hemorphin analog that could be used as a template for future modification and preparation of compounds with potential analgesic and anticonvulsant activity.
ABSTRACT
A study of the formation of copper (II) complexes with hemorphin peptide motifs in alkalic water solutions is presented. The effect of the peptide ligand on the complexing properties of the Cu (II) ion was quantified by giving the stoichiometry and stability of the complex compounds in the medium in which they are formed using voltammetric (cyclic) and spectral (UV-Vis and fluorimetric) analytical techniques. The resulting complexes were examined via IR spectroscopy to detect M-N and M-O oscillations and using the EPR approach in solution and in the solid phase to view the coordination and ligand binding regime. The possibility of the synergistic action of copper ions in the antivirus protection processes of cotton fibers coated in the same solvent with the newly obtained complex compounds was also investigated. One of the advantages is the formation of the complexes in an environment where the immobilization takes place, which contributes to increasing the efficiency of the process. The obtained results may serve as an aid for future more detailed biological studies of structure-activity relationships (SARs).
ABSTRACT
This manuscript presented the synthesis and characterization of two new N- and C-modified analogues of VV-hemorphin-7 containing RGD (Arg-Gly-Asp) residues as potential nociceptive agents and bioactive materials. It has been shown that the addition of one or two RGD sequences to natural VV-hemorphin-7 increases its effect on acute nociception, but the reduction of the inflammatory phase depends on the concentration of the peptide. The structure-property relationship of the new peptide derivatives was highlighted by electrochemical and FT-IR methods of analysis. Because of the proven bone-structural bonds of hydroxyapatite, the simultaneous deposition of peptide/hydroxyapatite on the surface of a titanium surface was investigated. The deposition was performed in a medium of gelatin solution containing dissolved amounts of peptide and hydroxyapatite using ultrasound. SEM-EDS analyzes confirmed the presence of a layer of the studied system.
Subject(s)
Oligopeptides , Titanium , Titanium/chemistry , Spectroscopy, Fourier Transform Infrared , Oligopeptides/chemistry , Peptides , Analgesics/pharmacology , HydroxyapatitesABSTRACT
The endogenous hemorphins are bioactive peptides with activity on opioid receptors. They are extensively studied and summarized in numerous reviews. During the last decade, several research teams have synthesized, characterized, and pharmacologically evaluated synthetic hemorphin analogs containing unusual amino acids, D-amino acids, α-aminophosphonic acids, and their derivatives. The present review summarizes the current studies on short-chain synthetic hemorphin peptide derivates containing non-natural amino acids. This review focuses on the structure-activity relationship analysis, details on specific methods for their characterization, and the advantage of synthetic hemorphin analogs compared to endogenous peptides as potent biologically active compounds with a complex mechanism of action.
ABSTRACT
The emergence of diverse peptide derivatives has been due to constant efforts to find a specific peptide with pronounced biological activity for effective application as a therapeutic. Spinorphin-peptide products have been reported to possess various applications and properties. In the present study, spinorphin peptides with a rhodamine residue and a modification in the amino acid backbone were synthesized by a solid-phase method using Fmoc chemistry. The results obtained from the spectral and electrochemical techniques used: Scanning electron microscopy (SEM), UV-vis, fluorescence, infrared spectroscopy (IR), and voltammetry were used to elucidate the structural characteristics and some physicochemical properties to gain insight into their behavior in the solid state and in aqueous solutions with different pHs. Both Rh-S5 and Rh-S6 had compound anticonvulsant effect comparable to Rh-S against psychomotor seizures at the highest dose of 20 µg. Furthermore, Rh-S6 showed a strong ability to inhibit seizure propagation and had a similar threshold to Rh-S against the intravenous pentylenetetrazol induced clonic seizure in mice; one of the three hybrid spinorphin analogs tested when screened for anticonvulsant activity. Biological tests against several bacterial pathogens such as Staphylococcus aureus, Escherichia coli, and Bacillus cereus showed similar results to negative control of the new peptide derivatives. The compounds also showed weak activity against Candida albicans fungus. The antioxidant testing results revealed more than 50% activity by reviewing the radical deterrence capabilities of 2,2-diphenyl-1-picrylhydrazyl (DPPH). The results are indicative of the ongoing search for universal antimicrobial agents with pronounced synergism when used simultaneously as anticonvulsant, antibacterial, and antifungal agents.
ABSTRACT
New analogues of the endogenous heptapeptide VV-hemorphin-5 (valorphin) synthesised by amino acid replacement allow for tailoring the peptide activity in vivo. Investigation of hemorphin-induced alterations of lipid bilayers' physicochemical parameters unravels membrane-mediated mechanisms of interaction with cells and subcellular structures. We studied the effect of modified valorphins with nociceptive activity on the structure, mechanical and electrical properties of lipid membrane models. Lower bending rigidity and higher specific capacitance of phosphatidylcholine bilayers were found in the presence of VV-hemorphin-5 analogues. Peptide partition constants for the transfer from the aqueous solution into the membrane were determined by isothermal titration calorimetry. It was found that the inclusion of non-proteinogenic acids with different number of methylene groups lead to alterations of hemorphin-membrane binding. The highest membrane affinity was obtained for a hemorphin derivative with dose-dependent variable effects on visceral nociception in mice. The valorphin analogue with the most pronounced anti-nociceptive effect in vivo induced the highest dipole and zeta potential change without significantly affecting the lipid packing at glycerol level in phosphatidylcholine bilayers.
Subject(s)
Hemoglobins , Phosphatidylcholines , Animals , Mice , Hemoglobins/chemistry , Cell Membrane/metabolism , Lipid BilayersABSTRACT
Some new N- and C-modified biomolecular peptide analogues of both VV-hemorphin-5 and VV-hemorphin-7 with varied amino acids (Cys, Glu, His), 1-adamantanecarboxylic acid, and niacin (nicotinic acid) were synthesized by solid-phase peptide synthesis-Fmoc (9-fluorenylmethoxy-carbonyl) chemistry and were characterized in water solutions with different pH using spectroscopic and electrochemical techniques. Basic physicochemical properties related to the elucidation of the peptide structure at physiological pH have been also studied. The results showed that the interaction of peptide compounds with light and electricity preserves the structural and conformational integrity of the compounds in the solutions. Moreover, textile cotton fibers were modified with the new compounds and the binding of the peptides to the surface of the material was proved by FTIR and SEM analysis. Washing the material with an alkaline soap solution did not show a violation of the modified structure of the cotton. Antiviral activity against the human respiratory syncytial virus (HRSV-S2) and human adenovirus serotype 5 (HAdV-5), the antimicrobial activity against B. cereus and P. aeruginosa used as model bacterial strains and cytotoxic effect of the peptide derivatives and modified cotton textile material has been evaluated. Antimicrobial tests showed promising activity of the newly synthesized compounds against the used Gram-positive and Gram-negative bacteria. The compounds C-V, H-V, AC-V, and AH-V were found slightly more active than NH7C and NCH7. The activity has been retained after the deposition of the compounds on cotton fibers.
Subject(s)
Anti-Infective Agents , Gram-Negative Bacteria , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Cotton Fiber , Gram-Positive Bacteria , Humans , TextilesABSTRACT
In the present study, a series of new analogues of both LVV- and VV-hemorphin-7 have been synthesized and characterized. They were modified at the N- and C-terminus with varied amino acids (Ile, D-Leu, D-Val, D-Phe) and enantiopure chiral S- and R- α-aminophosphonic acids ((dimethoxyphosphoryl)methyl)-valine and ((dimethoxyphosphoryl) methyl)-leucine) to optimize the physicochemical properties and to enhance their anticonvulsant potency. The novel peptide analogues were prepared by solid-phase peptide synthesis-Fmoc-strategy. Their structure-property relationship was studied by FT-IR spectroscopy and electrochemical methods. The lipophilicity is also presented. The anticonvulsant activity of peptide analogues, administered intracerebroventricularly, at doses of 1, 2.5, and 5 µg/10 µL, respectively, was explored by 6-Hz psychomotor seizure test, maximal electroshock test (MES) and a timed intravenous pentylenetetrazole (ivPTZ) infusion test in mice. The potential neurological toxicity of the substances was checked by a rotarod test. The H7 was used as a positive control. The H7-1 peptide analogue was the most active molecule against the psychomotor seizures, while H7-6 and H7-7 showed comparable to the positive group H7 potency in the MES test. The H7-5 to H7-8 analogues at the two tested doses of 2.5 and 5 µg/10 µl raised the threshold against ivPTZ-induced myoclonic, clonic, and tonic seizures. None of the hemorphin analogues exhibited neurotoxicity in the rotarod test. In conclusion, our results suggest that modified at N- and C-terminus of certain amino acids in the hemorphin analogues have a crucial role as a basis to design new LVV- and VV-hemorphin-7 analogues for experimental and clinical use.
Subject(s)
Anticonvulsants , Hemoglobins , Animals , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Hemoglobins/chemistry , Mice , Pentylenetetrazole , Peptide Fragments , Spectroscopy, Fourier Transform Infrared , Structure-Activity RelationshipABSTRACT
Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.
Subject(s)
Diet , Genetic Loci , Obesity/genetics , Genome-Wide Association Study , Genotype , Humans , Nuclear Proteins/genetics , Phenotype , Polymorphism, Single NucleotideABSTRACT
Here we report on the synthesis and characterization of three new N-modified analogues of hemorphin-4 with rhodamine B. Modified with chloroacetyl, chloride cotton fabric has been dyed and color coordinates of the obtained textile materials were determined. Antiviral and virucidal activities of both the peptide-rhodamine B compounds and the dyed textile material were studied. Basic physicochemical properties (acid-base behavior, solvent influence, kinetics) related to the elucidation of structural activity of the new modified peptides based on their steric open/closed ring effect were studied. The obtained results lead to the conclusion that in protic solvent with change in pH of the environment, direct control over the dyeing of textiles can be achieved. Both the new hybrid peptide compounds and the modification of functionalized textile materials with these bioactive hemorphins showed virucidal activity against the human respiratory syncytial virus (HRSV-S2) and human adenovirus serotype 5 (HAdV-5) for different time intervals (30 and 60 min) and the most active compound was Rh-3.
Subject(s)
Adenoviridae/drug effects , Antiviral Agents/pharmacology , Peptides/pharmacology , Respiratory Syncytial Virus, Human/drug effects , Rhodamines/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Microbial Sensitivity Tests , Molecular Structure , Peptides/chemistry , Peptides/isolation & purification , Rhodamines/chemistry , Rhodamines/isolation & purification , Time FactorsABSTRACT
The dorsal vagal complex (DVC) in the hindbrain, composed of the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus, plays a critical role in modulating satiety. The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) act directly in the brain to modulate feeding, and receptors for both are expressed in the DVC. Given the impressive clinical responses to pharmacologic manipulation of incretin signaling, understanding the central mechanisms by which incretins alter metabolism and energy balance is of critical importance. Here, we review recent single-cell approaches used to detect molecular signatures of GLP-1 and GIP receptor-expressing cells in the DVC. In addition, we discuss how current advancements in single-cell transcriptomics, epigenetics, spatial transcriptomics, and circuit mapping techniques have the potential to further characterize incretin receptor circuits in the hindbrain.