Fate of bradykinin-potentiating peptide 9a after intravenous injection.
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ABSTRACT:
SUBMITTER: Martin LC
PROVIDER: S-EPMC1161860 | biostudies-other | 1979 Dec
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Snake venom is a source of many pharmacologically important molecules. Agkistrodon bilineatus commonly known as Cantil, is spread over Central America particularly in Mexico and Costa Rica. From the venom of Agkistrodon bilineatus we have isolated and characterised six hypotensive peptides, and two bradykinin inhibitor peptides. The IC-50 value of four synthesized peptides was studied, towards angiotensin converting enzyme, in order to study the structure-function relationship of these peptides. RESULTS:The purification of the peptides was carried out by size exclusion chromatography, followed by reverse phase chromatography. Sequences of all peptides were determined applying MALDI-TOF/TOF mass spectrometry. These hypotensive peptides bear homology to bradykinin potentiating peptides and venom vasodilator peptide. The peptide with m/z 1355.53 (M?+?H)(+1), and the corresponding sequence ZQWAQGRAPHPP, we identified for the first time. A precursor protein containing a fragment of this peptide was reported at genome level, (Uniprot ID P68515), in Bothrops insularis venom gland. These proline rich hypotensive peptides or bradykinin potentiating peptides are usually present in the venom of Crotalinae, and exhibit specificity in binding to the C domain of somatic angiotensin converting enzyme. Four of these hypotensive peptides, were selected and synthesized to obtain the required quantity to study their IC50 values in complex with the angiotensin converting enzyme. The peptide with the sequence ZLWPRPQIPP displayed the lowest IC50 value of 0.64 ?M. The IC50 value of the peptide ZQWAQGRAPHPP was 3.63 ?M. CONCLUSION:The canonical snake venom BPPs classically display the IPP motif at the C-terminus. Our data suggest that the replacement of the highly conserved hydrophobic isoleucine by histidine does not affect the inhibitory activity, indicating that isoleucine is not mandatory to inhibit the angiotensin converting enzyme. The evaluation of IC 50 values show that the peptide with basic pI value exhibits a lower IC 50 value.
| S-EPMC4712559 | biostudies-literature
Project description:Bradykinin-potentiating peptides (BPPs) are molecules discovered by Sergio Ferreira - who found them in the venom of Bothrops jararaca in the 1960s - that literally potentiate the action of bradykinin in vivo by, allegedly, inhibiting the angiotensin-converting enzymes. After administration, the global physiological effect of BPP is the decrease of the blood pressure. Due to this interesting effect, one of these peptides was used by David Cushman and Miguel Ondetti to develop a hypotensive drug, the widely known captopril, vastly employed on hypertension treatment. From that time on, many studies on BPPs have been conducted, basically describing new peptides and assaying their pharmacological effects, mostly in comparison to captopryl. After compiling most of these data, we are proposing that snake BPPs are 'modular' peptidic molecules, in which the combination of given amino acid 'blocks' results in the different existing peptides (BPPs), commonly found in snake venom. We have observed that there would be mandatory modules (present in all snake BPPs), such as the N-terminal pyroglutamic acid and C-terminal QIPP, and optional modules (amino acid blocks present in some of them), such as AP or WAQ. Scattered between these modules, there might be other amino acids that would 'complete' the peptide, without disrupting the signature of the classical BPP. This modular arrangement would represent an important evolutionary advantage in terms of biological diversity that might have its origins either at the genomic or at the post-translational modification levels. Regardless of the modules' origin, the increase in the diversity of peptides has definitely been essential for snakes' success on nature.
| S-EPMC5657115 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), a novel coronavirus responsible for the recent infectious pandemic, is known to downregulate angiotensin-converting enzyme-2 (ACE2). Most current investigations focused on SARS-COV-2-related effects on the renin-angiotensin system and especially the resultant increase in angiotensin II, neglecting its effects on the kinin-kallikrein system. SARS-COV-2-induced ACE2 inhibition leads to the augmentation of bradykinin 1-receptor effects, as ACE2 inactivates des-Arg9-bradykinin, a bradykinin metabolite. SARS-COV-2 also decreases bradykinin 2-receptor effects as it affects bradykinin synthesis by inhibiting cathepsin L, a kininogenase present at the site of infection and involved in bradykinin production. The physiologies of both the renin-angiotensin and kinin-kallikrein system are functionally related suggesting that any intervention aiming to treat SARS-COV-2-infected patients by triggering one system but ignoring the other may not be adequately effective. Interestingly, the snake-derived bradykinin-potentiating peptide (BPP-10c) acts on both systems. BPP-10c strongly decreases angiotensin II by inhibiting ACE, increasing bradykinin-related effects on the bradykinin 2-receptor and increasing nitric oxide-mediated effects. Based on a narrative review of the literature, we suggest that BPP-10c could be an optimally effective option to consider when aiming at developing an anti-SARS-COV-2 drug.
| S-EPMC7436322 | biostudies-literature
Project description:A bradykinin-potentiating peptide (BPP) from Amazon Bothrops atrox venom with m/z 1384.7386 was identified and characterized by collision induced dissociation (CID) using an ESI-MS/MS spectra obtained in positive ion mode on a hybrid Qq-oaTOF mass spectrometer, Xevo G2 QTof MS (Waters, Manchester, UK). De novo peptide sequence analysis of the CID fragmentation spectra showed the amino acid sequence ZKWPRPGPEIPP, with a pyroglutamic acid and theoretical monoisotopic m/z 1384.7378, which is similar to experimental data, showing a mass accuracy of 0.6 ppm. The peptide is homologous to other BPP from Bothrops moojeni and was named as BPP-BAX12.
| S-EPMC3640538 | biostudies-literature
Project description:A 1.8-kb cDNA clone was isolated from a Bothrops jararaca venom gland cDNA library that encodes a 256-aa precursor for bradykinin-potentiating peptides (angiotensin-converting enzyme inhibitors) and a C-type natriuretic peptide (CNP). The seven bradykinin-potentiating peptides are aligned tandemly after the hydrophobic signal peptide sequence, followed by a putative intervening sequence and a CNP at the C terminus. Northern blot analysis indicated the predominant expression of a 1.8-kb mRNA in the venom glands as well as in the spleen and the brain. Two lower intensity mRNA bands of 3.5 kb and 5.7 kb also hybridized to the cDNA clone. Radioimmunoassay for the CNP was performed using the antiserum against rat CNP. The presence of CNP immunoreactivity was detected in the low molecular weight fraction of the Bothrops jararaca venom.
| S-EPMC19766 | biostudies-literature
Project description:Ion mobility and mass spectrometry techniques are used to investigate the stabilities of different conformations of bradykinin (BK, Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9). At elevated solution temperatures, we observe a slow protonation reaction, i.e., [BK+2H]2++H+ → [BK+3H]3+, that is regulated by trans → cis isomerization of Arg1-Pro2, resulting in the Arg1- cis-Pro2- cis-Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 (all- cis) configuration. Once formed, the all- cis [BK+3H]3+ spontaneously cleaves the bond between Pro2-Pro3 with perfect specificity, a bond that is biologically resistant to cleavage by any human enzyme. Temperature-dependent kinetics studies reveal details about the intrinsic peptide processing mechanism. We propose that nonenzymatic cleavage at Pro2-Pro3 occurs through multiple intermediates and is regulated by trans → cis isomerization of Arg1-Pro2. From this mechanism, we can extract transition state thermochemistry: Δ G‡ = 94.8 ± 0.2 kJ·mol-1, Δ H‡ = 79.8 ± 0.2 kJ·mol-1, and Δ S‡ = -50.4 ± 1.7 J·mol-1·K-1 for the trans → cis protonation event; and, Δ G‡ = 94.1 ± 9.2 kJ·mol-1, Δ H‡ = 107.3 ± 9.2 kJ·mol-1, and Δ S‡ = 44.4 ± 5.1 J·mol-1·K-1 for bond cleavage. Biological resistance to the most favored intrinsic processing pathway prevents formation of Pro3-Gly4-Phe5-Ser6- cis-Pro7-Phe8-Arg9 that is approximately an order of magnitude more antigenic than BK.
| S-EPMC6503673 | biostudies-literature
Project description:RATIONALE:Addictive drugs are commonly delivered in the organism by means of intravenous (i.v.) injections. Since saline mimics the blood environment by basic ionic properties and pH, it is generally assumed that it should not have any physiological effects, serving as a control for the effects induced by drugs. OBJECTIVE:The aim of the study was to examine central, behavioral, and physiological effects of stress- and cue-free i.v. saline injection in freely moving rats. METHODS:We examined how a typical low-volume and slow-speed saline injections affect cortical electroencephalograpy (EEG), neck electromyography (EMG), locomotor activity as well as central and peripheral temperatures. RESULTS:Saline injection made during slow-wave synchronized activity induces rapid transient EEG desynchronization, manifesting as a drop of EEG total power, decrease in alpha activity, and increases in beta and gamma activities. Saline injection did not affect locomotor activity as well as brain and body temperatures, but induced a transient increase in neck EMG activity and a rapid brief drop in skin temperature, suggesting peripheral vasoconstriction. These responses were virtually fully absent when saline injection was made during naturally occurring desynchronized EEG activity during behavioral activity. CONCLUSIONS:Since i.v. injection is able to produce a peripheral sensory signal that is transmitted rapidly to the CNS and followed by a more prolonged effect of the injected drug on brain cells, with repeated drug administrations, the injection itself could play a role of drug-related sensory cue, thus inducing conditioned physiological responses and altering the effects of injected drugs.
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Project description:Gene therapy for genetic deafness is a promising approach by which to prevent hearing loss or to restore hearing after loss has occurred. Although a variety of direct approaches to introduce viral particles into the inner ear have been described, presumed physiological barriers have heretofore precluded investigation of systemic gene delivery to the cochlea. In this study, we sought to characterize systemic delivery of a rAAV2/9 vector as a non-invasive means of cochlear transduction. In wild-type neonatal mice (postnatal day 0-1), we show that intravenous injection of rAAV2/9 carrying an eGFP-reporter gene results in binaural transduction of inner hair cells, spiral ganglion neurons and vestibular hair cells. Transduction efficiency increases in a dose-dependent manner. Inner hair cells are transduced in an apex-to-base gradient, with transduction reaching 96% in the apical turn. Hearing acuity in treated animals is unaltered at postnatal day 30. Transduction is influenced by viral serotype and age at injection, with less efficient cochlear transduction observed with systemic delivery of rAAV2/1 and in juvenile mice with rAAV2/9. Collectively, these data validate intravenous delivery of rAAV2/9 as a novel and atraumatic technique for inner ear transgene delivery in early postnatal mice.
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Project description:Levels of nerve growth factor (NGF) are elevated in inflamed tissues. In sensory neurons, increases in NGF augment neuronal sensitivity (sensitization) to noxious stimuli. Here, we hypothesized that NGF also sensitizes sympathetic neurons to proinflammatory stimuli. We cultured superior cervical ganglion (SCG) neurons from adult male Sprague Dawley rats with or without added NGF and compared their responsiveness to bradykinin, a proinflammatory peptide. The NGF-cultured neurons exhibited significant depolarization, bursts of action potentials, and Ca(2+) elevations after bradykinin application, whereas neurons cultured without NGF showed only slight changes in membrane potential and cytoplasmic Ca(2+) levels. The NGF effect, which requires trkA receptors, takes hours to develop and days to reverse. We addressed the ionic mechanisms underlying this sensitization. NGF did not alter bradykinin-induced M-current inhibition or phosphatidylinositol 4,5-bisphosphate hydrolysis. Maxi-K channel-mediated current evoked by depolarizations was reduced by 50% by culturing neurons in NGF. Application of iberiotoxin or paxilline, blockers of Maxi-K channels, mimicked NGF treatment and sensitized neurons to bradykinin application. A calcium channel blocker also mimicked NGF treatment. We found that NGF reduces Maxi-K channel opening by decreasing the activity of nifedipine-sensitive calcium channels. In conclusion, culture in NGF reduces the activity of L-type calcium channels, and secondarily, the calcium-sensitive activity of Maxi-K channels, rendering sympathetic neurons electrically hyper-responsive to bradykinin.
| S-EPMC4152604 | biostudies-literature
Project description:Stem cell transplantation showed promising results in IBD management. However, the therapeutic impacts of cell delivery route that is critical for clinical translation are currently poorly understood. Here, three different MSCs delivery routes: intraperitoneal (IP), intravenous (IV), and anal injection (AI) were compared on DSS-induced colitic mice model. The overall therapeutic factors, MSCs migration and targeting as well as local immunomodulatory cytokines and FoxP3(+) cells infiltration were analyzed. Colitis showed varying degrees of alleviation after three ways of MSCs transplantation, and the IP injection showed the highest survival rate of 87.5% and displayed the less weight loss and quick weight gain. The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group. The fluorescence imaging disclosed higher intensity of engrafted cells in inflamed colon and the corresponding mesentery lymph nodes (MLNs) in IP and AI groups than the IV group. Real time-PCR and ELISA also demonstrate lower TNF-α and higher IL-10, TSG-6 levels in IP group. The immunohistochemistry indicated higher repair proliferation (Ki-67) and more FoxP3(+) cells accumulation of IP group. IP showed better colitis recovery and might be the optimum MSCs delivery route for the treatment of DSS-induced colitis.
| S-EPMC4973258 | biostudies-literature