-
FEBS Letters Jan 2024Human somatic angiotensin-1-converting enzyme (sACE) is composed of a catalytic N-(nACE) and C-domain (cACE) of similar size with different substrate specificities. It...
Human somatic angiotensin-1-converting enzyme (sACE) is composed of a catalytic N-(nACE) and C-domain (cACE) of similar size with different substrate specificities. It is involved in the regulation of blood pressure by converting angiotensin I to the vasoconstrictor angiotensin II and has been a major focus in the development of therapeutics for hypertension. Bioactive peptides from various sources, including milk, have been identified as natural ACE inhibitors. We report the structural basis for the role of two lacototripeptides, Val-Pro-Pro and Ile-Pro-Pro, in domain-specific inhibition of ACE using X-ray crystallography and kinetic analysis. The lactotripeptides have preference for nACE due to altered polar interactions distal to the catalytic zinc ion. Elucidating the mechanism of binding and domain selectivity of these peptides also provides important insights into the functional roles of ACE.
Topics: Humans; Peptidyl-Dipeptidase A; Kinetics; Angiotensin-Converting Enzyme Inhibitors; Angiotensins
PubMed: 37904282
DOI: 10.1002/1873-3468.14768 -
Molecules (Basel, Switzerland) Jul 2023Atlantic sea cucumber is a benthic marine echinoderm found in Northwest Atlantic waters and is harvested mainly for its body wall. The body wall, along with internal...
Atlantic sea cucumber is a benthic marine echinoderm found in Northwest Atlantic waters and is harvested mainly for its body wall. The body wall, along with internal organs and aquaphyrangeal bulb/flower, is a rich source of proteins, where the latter parts are often considered as processing discards. The objective of this research was to produce protein hydrolysates from sea cucumber tissues (body wall, flower, and internal organs) with bioactive properties associated with antioxidants, DNA and LDL cholesterol oxidation inhibition, and angiotensin-I-converting enzyme (ACE) inhibitory effects. The protein hydrolysates were prepared using food-grade commercial enzymes, namely Alcalase, Corolase, and Flavourzyme, individually and in combination, and found that the combination of enzymes exhibited stronger antioxidant potential than the individual enzymes, as well as their untreated counterparts. Similar trends were also observed for the DNA and LDL cholesterol oxidation inhibition and ACE-inhibitory properties of sea cucumber protein hydrolysates, mainly those that were prepared from the flower. Thus, the findings of this study revealed potential applications of sea cucumber-derived protein hydrolysates in functional foods, nutraceuticals, and dietary supplements, as well as natural therapeutics.
Topics: Animals; Antioxidants; Angiotensin-Converting Enzyme Inhibitors; Cucumaria; Sea Cucumbers; Protein Hydrolysates; Cholesterol, LDL; Peptidyl-Dipeptidase A
PubMed: 37446924
DOI: 10.3390/molecules28135263 -
Journal of Microbiology, Immunology,... Dec 2023SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an...
BACKGROUND
SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an inflammatory process. Angiotensin-(1-7) may have an anti-inflammatory effect through activation of Mas receptor. This study aims to investigate whether SARS-CoV-2 SP can induce inflammation through ACE2 in the alveolar epithelial cells which can be modulated through angiotensin-(1-7)/Mas receptor axis.
METHODS
HPAEpiC were treated with SARS-CoV-2 SP in the presence or absence of ACE2 antagonist-dalbavancin and Mas receptor agonist-angiotensin-(1-7). Proinflammatory cytokine production (IL-6 and IL-8) were measured at mRNA and protein levels. MAP kinase phosphorylation and transcription factor activation was determined by Western Blot. Mas receptor was blocked by either antagonist (A779) or knockdown (specific SiRNA). Experiments were replicated using A549 cells.
FINDINGS
SARS-CoV-2 SP (5 μg/mL) significantly induced MAP kinase (ERK1/2) phosphorylation, downstream transcription factor (activator protein-1, AP-1) activation and cytokine production (IL-6 and IL-8) at both mRNA and protein levels. Pretreatment with dalbavancin (10 μg/mL), or angiotensin-(1-7) (10 μM) significantly reduced ERK1/2 phosphorylation, AP-1 activation, and cytokine production. However, these angiotensin-(1-7)-related protective effects were significantly abolished by blocking Mas receptor with either antagonist (A799,10 μM) or SiRNA knockdown.
INTERPRETATION
SARS-CoV-2 SP can induce proinflammatory cytokine production, which can be inhibited by either ACE2 antagonist or Mas receptor agonist-angiotensin-(1-7). Angiotensin-(1-7)-related protective effect on cytokine reduction can be abolished by blocking Mas receptor. Our findings suggest that ACE2/angiotensin-(1-7)/Mas axis may serve as a therapeutic target to control inflammatory response triggered by SARS-CoV-2 SP.
Topics: Humans; Alveolar Epithelial Cells; Angiotensin-Converting Enzyme 2; COVID-19; Cytokines; Interleukin-6; Interleukin-8; Peptidyl-Dipeptidase A; RNA, Messenger; RNA, Small Interfering; RNA, Viral; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Transcription Factor AP-1
PubMed: 37802686
DOI: 10.1016/j.jmii.2023.09.003 -
European Journal of Pharmacology Jan 2024Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by diffuse alveolar inflammation, fibroblast differentiation, and the excessive...
Pulmonary fibrosis (PF) is a chronic, progressive interstitial lung disease characterized by diffuse alveolar inflammation, fibroblast differentiation, and the excessive deposition of extracellular matrix. During the progression of PF, redox imbalance caused by excessive reactive oxygen species (ROS) production can result in further destruction of lung tissue. At present, data on the role of NADPH oxidase-4 (Nox4)-nuclear factor erythroid 2-related factor 2 (Nrf2) redox imbalance in PF are limited. The angiotensin (1-7) [Ang-(1-7)]/Mas axis is a protective axis in the renin-angiotensin system (RAS) that exerts antifibrotic effects. Therefore, this study aimed to investigate the role of the Ang-(1-7)/Mas axis in PF and to explore its mechanism in depth. The results revealed that the Ang-(1-7)/Mas axis inhibited TGF-β1-induced lung fibroblast differentiation, inflammation and fibrosis in bleomycin (BLM)-treated lung tissue. A mechanistic study suggested that the Ang-(1-7)/Mas axis may restore Nox4-Nrf2 redox homeostasis by upregulating the level of p62, reducing oxidative stress and the inflammatory response and thus delaying the progression of lung fibrosis. This study provides a theoretical basis for exploring the mechanisms of PF and therapeutic targets for PF.
Topics: Mice; Animals; Pulmonary Fibrosis; NF-E2-Related Factor 2; Bleomycin; Peptidyl-Dipeptidase A; Lung; Inflammation; Oxidation-Reduction; Homeostasis; NADPH Oxidase 4
PubMed: 38043775
DOI: 10.1016/j.ejphar.2023.176233 -
Foods (Basel, Switzerland) Nov 2023Hypertension is a widespread health risk, affecting over a billion people and causing 9 million deaths per year. The Renin-Angiotensin-Aldosterone System (RAAS) is a...
Hypertension is a widespread health risk, affecting over a billion people and causing 9 million deaths per year. The Renin-Angiotensin-Aldosterone System (RAAS) is a primary target for hypertension treatment, and it is primarily treated through drugs that inhibit the Angiotensin I-Converting Enzyme (ACE). In addition to pharmacological treatment, various plants are recommended in traditional medicine for blood pressure regulation. This study aimed to produce high-phenolic-content extracts with and without enzymatic assistance from red grape pomace and evaluate their antioxidant capacity and ACE inhibitory potential. The total phenolic content (TPC) was measured, and phenolic identification was performed using HPLC analysis. In addition, the antioxidant capacity and anti-hypertensive potential were determined via in vitro assays. There was no statistical difference in the TPC antioxidant capacity between the extraction methods. Otherwise, when considering the extraction yield, the enzymatic process recovered around 70% more phenolic compounds from the pomace, and the phenolic profile was changed. Enzymatic assistance also significantly increased the ACE inhibitory potential in the grape pomace extract. This study demonstrates the viability of upcycling grape pomace to obtain bioactive compounds and to reduce their environmental impact, and highlights the influence of the enzymatic extraction on the hypotensive potential of the extract.
PubMed: 38002167
DOI: 10.3390/foods12224109 -
Frontiers in Endocrinology 2023Twin gestation is related to a higher risk of hypertensive disorders in pregnancy with possible risk stratification depending on chorionicity. It may be related to... (Observational Study)
Observational Study
INTRODUCTION
Twin gestation is related to a higher risk of hypertensive disorders in pregnancy with possible risk stratification depending on chorionicity. It may be related to differences in plasma renin-angiotensin-aldosterone components between monochorionic and dichorionic twin pregnancies. The study aimed to analyze the plasma ANG II and ANG 1-7 concentrations in women with monochorionic and dichorionic twin gestation.
METHODS
A prospective observational study included 79 women between 32 and 34 weeks of gestation with twin pregnancy (31 with monochorionic gestation and 48 with dichorionic gestation). Angiotensin II and angiotensin 1-7 concentrations were measured in the collected blood samples.
RESULTS
No significant differences were observed in angiotensin II concentrations between the dichorionic and monochorionic group with significantly higher levels of angiotensin 1-7 being observed in the dichorionic group. Angiotensin 1-7 level was higher than angiotensin II in 20 women (64.5%) in the monochorionic group and in 42 women (87.5%, p=0.01) in the dichorionic group. Higher plasma concentrations of angiotensin II and lower concentrations of angiotensin 1-7 were found in 5 women with gestational hypertension and in 3 with preeclampsia compared to normotensive women.
DISCUSSION
It is the first study investigating angiotensin II and angiotensin 1-7 in twin pregnancies regarding chorionicity. Our results showed that plasma angiotensin 1-7 concentration was related to chorionicity, while plasma angiotensin II level was not. In most women with twin gestation angiotensin 1-7 concentration exceeded the concentration of angiotensin II. A switch in the relation between angiotensin II and angiotensin 1-7 was observed in hypertensive pregnant women.
Topics: Pregnancy; Female; Humans; Pregnancy, Twin; Angiotensin II; Pregnancy Trimester, Third; Peptide Hormones; Hypertension, Pregnancy-Induced; Angiotensin I; Peptide Fragments
PubMed: 38260128
DOI: 10.3389/fendo.2023.1329025 -
International Journal of Molecular... Oct 2023Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate...
PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease.
Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.
Topics: Humans; Mice; Female; Animals; Oxaliplatin; Cancer Pain; Disease Models, Animal; Mice, Inbred C57BL; Neuralgia; Hyperalgesia; Breast Neoplasms; Bone Neoplasms; Antineoplastic Agents
PubMed: 37834455
DOI: 10.3390/ijms241915007 -
Molecules (Basel, Switzerland) Oct 2023Angiotensin-converting enzyme 1 (ACE1) is a peptide involved in fluid and blood pressure management. It regulates blood pressure by converting angiotensin I to...
Detection of Various Traditional Chinese Medicinal Metabolites as Angiotensin-Converting Enzyme Inhibitors: Molecular Docking, Activity Testing, and Surface Plasmon Resonance Approaches.
Angiotensin-converting enzyme 1 (ACE1) is a peptide involved in fluid and blood pressure management. It regulates blood pressure by converting angiotensin I to angiotensin II, which has vasoconstrictive effects. Previous studies have shown that certain compounds of natural origin can inhibit the activity of angiotensin-converting enzymes and exert blood pressure-regulating effects. Surface Plasmon Resonance (SPR) biosensor technology is the industry standard method for observing biomolecule interactions. In our study, we used molecular simulation methods to investigate the docking energies of various herbal metabolites with ACE1 proteins, tested the real-time binding affinities between various herbal metabolites and sACE1 by SPR, and analyzed the relationship between real-time binding affinity and docking energy. In addition, to further explore the connection between inhibitor activity and real-time binding affinity, several herbal metabolites' in vitro inhibitory activities were tested using an ACE1 activity test kit. The molecular docking simulation technique's results and the real-time affinity tested by the SPR technique were found to be negatively correlated, and the virtual docking technique still has some drawbacks as a tool for forecasting proteins' affinities to the metabolites of Chinese herbal metabolites. There may be a positive correlation between the enzyme inhibitory activity and the real-time affinity detected by the SPR technique, and the results from the SPR technique may provide convincing evidence to prove the interaction between herbal metabolites and ACE1 target proteins.
Topics: Angiotensin-Converting Enzyme Inhibitors; Molecular Docking Simulation; Surface Plasmon Resonance; Biosensing Techniques; Angiotensins
PubMed: 37894610
DOI: 10.3390/molecules28207131 -
Antiviral Research Apr 2024The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to...
The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on α-dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of α-dystroglycan (α-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2). Prophylactic and therapeutic administration of α-DGN reduced SARS-CoV-2 lung titres and protected the mice from respiratory symptoms and death. Recombinant α-DGN also blocked infection of a wide range of enveloped viruses including the four Dengue virus serotypes, influenza A virus, respiratory syncytial virus, tick-borne encephalitis virus, but not human adenovirus, a non-enveloped virus in vitro. This study establishes soluble recombinant α-DGN as a broad-band, natural compound candidate therapeutic against enveloped viruses.
Topics: Mice; Animals; Humans; SARS-CoV-2; COVID-19; Dystroglycans; Pandemics; Escherichia coli; Mice, Transgenic; Antiviral Agents
PubMed: 38387750
DOI: 10.1016/j.antiviral.2024.105837 -
BioRxiv : the Preprint Server For... Jun 2024Multi-step multi-hour tryptic proteolysis has limited the utility of bottom-up proteomics for cases that require immediate quantitative information. The recently...
UNLABELLED
Multi-step multi-hour tryptic proteolysis has limited the utility of bottom-up proteomics for cases that require immediate quantitative information. The recently available hyperthermoacidic (HTA) protease "Krakatoa" digests samples in a single 5 to 30-minute step at pH 3 and >80 °C; conditions that disrupt most cells and tissues, denature proteins, and block disulfide reformation. The combination of quick single-step sample preparation with high throughput dual trapping column single analytical column (DTSC) liquid chromatography-mass spectrometry (LC-MS) achieves "Rapid Proteomics" in which the time from sample collection to actionable data is less than 1 hour. The presented development and systematic evaluation of this methodology found reproducible quantitation of over 160 proteins from just 1 microliter of whole blood. Furthermore, the preference of the HTA-protease for intact proteins over peptides allows for sensitive targeted quantitation of the Angiotensin I and II bioactive peptides in under half an hour. With these methods we analyzed serum and plasma from 53 individuals and quantified Angiotensin and proteins that were not detected with trypsin. This assessment of Rapid Proteomics suggests that concentration of circulating protein and peptide biomarkers could be measured in almost real-time by LC-MS.
TOC FIGURE
Rapid proteomics enables near real-time monitoring of circulating blood biomarkers. One microliter of blood is collected every 8 minutes, digested for 20 minutes, and then analyzed by targeted mass spectrometry for 8 minutes. This results in a 30-minute delay with datapoints every 8 minutes.
PubMed: 38853916
DOI: 10.1101/2024.06.01.596979