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Viruses Oct 2023Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme...
Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4-, and Treg CD8-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.
Topics: Humans; Mice; Animals; Lipoxygenase Inhibitors; SARS-CoV-2; COVID-19; Lung; Mice, Transgenic; Immunity, Innate; Weight Loss; Disease Models, Animal
PubMed: 37896826
DOI: 10.3390/v15102049 -
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 -
Marine Drugs Sep 2023The objective of this study was to isolate and characterize collagen and angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) peptides from the swim bladders of...
Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from the Collagens of Monkfish () Swim Bladders: Isolation, Characterization, Molecular Docking Analysis and Activity Evaluation.
The objective of this study was to isolate and characterize collagen and angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) peptides from the swim bladders of monkfish (). Therefore, acid-soluble collagen (ASC-M) and pepsin-soluble collagen (PSC-M) with yields of 4.27 ± 0.22% and 9.54 ± 0.51%, respectively, were extracted from monkfish swim bladders using acid and enzyme methods. The ASC-M and PSC-M contained Gly (325.2 and 314.9 residues/1000 residues, respectively) as the major amino acid, but they had low imino acid content (192.5 and 188.6 residues/1000 residues, respectively) in comparison with collagen from calf skins (CSC) (216.6 residues/1000 residues). The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns and ultraviolet (UV) absorption spectrums of ASC-M and PSC-M illustrated that they were mainly composed of type I collagen. Subsequently, three ACEi peptides were isolated from a PSC-M hydrolysate prepared via a double-enzyme system (alcalase + neutrase) and identified as SEGPK (MHP6), FDGPY (MHP7) and SPGPW (MHP9), with molecular weights of 516.5, 597.6 and 542.6 Da, respectively. SEGPK, FDGPY and SPGPW displayed remarkable anti-ACE activity, with IC values of 0.63, 0.94 and 0.71 mg/mL, respectively. Additionally, a molecular docking assay demonstrated that the affinities of SEGPK, FDGPY and SPGPW with ACE were -7.3, -10.9 and -9.4 kcal/mol, respectively. The remarkable ACEi activity of SEGPK, FDGPY and SPGPW was due to their connection with the active pockets and/or sites of ACE via hydrogen bonding, hydrophobic interaction and electrostatic force. Moreover, SEGPK, FDGPY and SPGPW could protect HUVECs by controlling levels of nitric oxide (NO) and endothelin-1 (ET-1). Therefore, this work provides an effective means for the preparation of collagens and novel ACEi peptides from monkfish swim bladders, and the prepared ACEi peptides, including SEGPK, FDGPY and SPGPW, could serve as natural functional components in the development of health care products to control hypertension.
Topics: Animals; Molecular Docking Simulation; Peptidyl-Dipeptidase A; Collagen; Fishes; Peptides; Acids; Angiotensins
PubMed: 37888451
DOI: 10.3390/md21100516 -
Frontiers in Oncology 2023Endometrial cancer (EC), the most common adenocarcinoma, represents 90% of uterine cancer in women with an increased incidence of occurrence attributed to age, obesity,... (Review)
Review
Endometrial cancer (EC), the most common adenocarcinoma, represents 90% of uterine cancer in women with an increased incidence of occurrence attributed to age, obesity, hypertension, and hypoestrogenism. Being the most common gynecological malignancy in women, it shows a relation with the activation of different components of the renin-angiotensin system (RAS), which is predominantly involved in maintaining blood pressure, salt, water, and aldosterone secretion, thereby playing a significant role in the etiology of hypertension. The components of the RAS, i.e., ACE-I, ACE-II, AT1R, AT2R, and Pro(renin) receptor, are widely expressed in both glandular and stromal cells of the endometrium, with varying levels throughout the different phases of the menstrual cycle. This causes the endometrial RAS to implicate angiogenesis, neovascularization, and cell proliferation. Thus, dysfunctioning of the endometrial RAS could predispose the growth and spread of EC. Interestingly, the increased expression of AngII, AGTR1, and AGTR2 showed advancement in the stages and progression of EC via the prorenin/ATP6AP2 and AngII/AGTR1 pathway. Therefore, this review corresponds to unraveling the relationship between the progression and development of endometrial cancer with the dysfunction in the expression of various components associated with RAS in maintaining blood pressure.
PubMed: 37869088
DOI: 10.3389/fonc.2023.1235418 -
Frontiers in Immunology 2023Sarcoidosis is a systemic inflammatory disease of unknown etiology, which mainly affects the lungs and lymph nodes, as well as extrapulmonary organs. Its incidence, and... (Review)
Review
Sarcoidosis is a systemic inflammatory disease of unknown etiology, which mainly affects the lungs and lymph nodes, as well as extrapulmonary organs. Its incidence, and prevalence rate, and disease course largely vary with regions and populations globally. The clinical manifestations of sarcoidosis depend on the affected organs and the degree of severity, and the diagnosis is mainly based on serum biomarkers, radiographic, magnetic resonance, or positron emission tomography imaging, and pathological biopsy. Noncaseating granulomas composing T cells, macrophages, epithelioid cells, and giant cells, were observed in a pathological biopsy, which was the characteristic pathological manifestation of sarcoidosis. Angiotensin-converting enzyme (ACE) was first found in the renin-angiotensin-aldosterone system. Its main function is to convert angiotensin I (Ang I) into Ang II, which plays an important role in regulating blood pressure. Also, an ACE insertion/deletion polymorphism exists in the human genome, which is involved in the occurrence and development of many diseases, including hypertension, heart failure, and sarcoidosis. The serum ACE level, most commonly used as a biomarker in diagnosing sarcoidosis, in patients with sarcoidosis increases. because of epithelioid cells and giant cells of sarcoid granuloma expressing ACE. Thus, it serves as the most commonly used biomarker in the diagnosis of sarcoidosis and also aids in analyzing its therapeutic effect and prognosis in patients with sarcoidosis.
Topics: Humans; Biomarkers; Granuloma; Lymph Nodes; Renin-Angiotensin System; Sarcoidosis; Peptidyl-Dipeptidase A
PubMed: 37868968
DOI: 10.3389/fimmu.2023.950095 -
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 -
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 -
Endokrynologia Polska 2023Recent studies have shown that a decline in isletβ cells quality is due to β-cell dedifferentiation, not only β-cell apoptosis. Angiotensin (1-7) [Ang(1-7)] could...
INTRODUCTION
Recent studies have shown that a decline in isletβ cells quality is due to β-cell dedifferentiation, not only β-cell apoptosis. Angiotensin (1-7) [Ang(1-7)] could attenuate high glucose-induced apoptosis and dedifferentiation of pancreaticβ cells by combining with MAS receptors. However, the mechanism of such action has not been elucidated. Recent studies have revealed that Wnt/β-catenin and forkhead box transcription factor O1 (FoxO1) are associated with β-cell dedifferentiation. Our study aims to explore whether the effects of Ang(1-7)on islet b cell dedifferentiation are mediated through the Wnt/β-catenin/FoxO1 pathway.
MATERIAL AND METHODS
Isletβ cells were divided into 6 groups: a control group, a high-glucose group, high glucose with Ang(1-7) group, high-glucose with Ang(1-7) and A779 group, high-glucose with angiotensin(1-7) and CHIR99021 group, and high-glucose with CHIR99021 group. A779 is a kind of MAS receptor antagonist that blocks the action of Ang(1-7), and CHIR99021 is a Wnt pathway activator. The morphology of pancreaticβ cells was observed in each group after 48 hours of intervention. β-cell insulin secretory function and expressions of relevant factors were measured.
RESULTS
Compared with the control group, the cell morphology became degraded in the high-glucose group and the capability of insulin secretion was reduced. Meanwhile, the expressions of matureβ cells markers [pancreatic and duodenal homeobox 1 (Pdx1) and MAF BZIP transcription factor A (MafA)] were reduced, while the expressions of endocrine progenitor cells makers [octamer-binding transcription factor 4 (Oct4) and Nanog] were increased. The addition of CHIR99021 resulted in profound deep destruction ofβ cells compared with the high-glucose group. However, such changes were dramatically reversed following the treatment of Ang(1-7). The addition of A779 significantly inhibited the improvement caused by Ang(1-7).
CONCLUSION
Ang(1-7) can effectively reverseβ cell dedifferentiation through Wnt/β-catenin/FoxO1 pathway. It might be a new strategy for preventing and treating diabetes.
Topics: Humans; Glucose; Wnt Signaling Pathway; Cell Dedifferentiation; beta Catenin; Insulin-Secreting Cells
PubMed: 37779373
DOI: 10.5603/ep.94750 -
Journal of Personalized Medicine Aug 2023Diabetic retinopathy (DR) is a complex and multifactorial pathology encompassing environmental, metabolic, and polygenic influences. Among the genes possibly involved in... (Review)
Review
No Association of Angiotensin-Converting Enzyme Insertion/Deletion (ACE I/D) Gene Polymorphism in the Susceptibility to Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients: An Updated Meta-Analysis.
Diabetic retinopathy (DR) is a complex and multifactorial pathology encompassing environmental, metabolic, and polygenic influences. Among the genes possibly involved in the development and progression of DR, the () gene stands out, which presents an insertion (I) or deletion (D) polymorphism of a 287 bp Alu repetitive sequence in intron 16. Thus, this study aimed to perform a systematic review with meta-analysis to elucidate the relationship between the gene (I/D) polymorphism (rs1799752) and the development and progression of DR in type 2 diabetic patients. PubMed/MEDLINE, Embase, Web of Science, and Scopus databases were systematically searched to retrieve articles that investigated the association between gene (I/D) polymorphism in DR patients. Sixteen articles were included in the systematic review. The results describe no significant association between the polymorphism and DR risk (OR = 1.12; CI = 0.96-1.31; and = 0.1359) for genotypic analysis by the dominant model (II vs. ID+DD). Moreover, we also observed no significant association between the D allele on the allele frequency analysis (I vs. D) and the DR risk (OR = 1.10; CI = 0.98-1.23; and = 0.1182). Forest plot analysis revealed that the discrepancy between previous studies most likely arose from variations in their sample sizes. In conclusion, I/D polymorphism appears to be not involved in the susceptibility to and progression of the DR in type 2 diabetic patients.
PubMed: 37763076
DOI: 10.3390/jpm13091308 -
Discovery of ACE Inhibitory Peptides Derived from Green Coffee Using In Silico and In Vitro Methods.Foods (Basel, Switzerland) Sep 2023Inhibition of angiotensin-I converting enzyme (ACE) is an important means of treating hypertension since it plays an important regulatory function in the...
Inhibition of angiotensin-I converting enzyme (ACE) is an important means of treating hypertension since it plays an important regulatory function in the renin-angiotensin system. The aim of this study was to investigate the ACE inhibitory effect of bioactive peptides from green coffee beans using in silico and in vitro methods. Alcalase and thermolysin were employed to hydrolyze protein extract from coffee beans. Bioactive peptides were identified by LC-MS/MS analysis coupled with database searching. The potential bioactivities of peptides were predicted by in silico screening, among which five novel peptides may have ACE inhibitory activity. In vitro assay was carried out to determine the ACE inhibitory degree. Two peptides (IIPNEVY, ITPPVMLPP) were obtained with IC values of 57.54 and 40.37 μM, respectively. Furthermore, it was found that two inhibitors bound to the receptor protein on similar sites near the S1 active pocket of ACE to form stable enzyme-peptide complexes through molecular docking, and the Lineweaver-Burk plot showed that IIPNEVY was a noncompetitive inhibitor, and ITPPVMLPP was suggested to be a mixed-type inhibitor. Our study demonstrated that two peptides isolated from coffee have potential applications as antihypertensive agents.
PubMed: 37761189
DOI: 10.3390/foods12183480