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Objective: This scoping review aims to comprehensively map the existing literature on the mechanisms of action of Alamandine (ALA), a peptide within the renin–angiotensin system, and its effects across various physiological systems. Materials and Methods: Utilizing the Joanna Briggs Institute methodology, a thorough search of databases including PubMed, Embase, Scopus, and Web of Science was conducted up to 30 January 2025. The review focused on identifying studies that explore the biological and therapeutic roles of ALA in different contexts, incorporating in vivo, in vitro, and in silico research. Results: A total of 590 records were initially identified, with 25 meeting the eligibility criteria for inclusion in this review. China emerged as the leading contributor to the research in this area, with a significant focus on the cardiovascular system. The studies revealed that ALA exhibits a range of beneficial effects, including anti-inflammatory, vasodilatory, antifibrotic, and antiapoptotic actions. These effects are primarily mediated through the inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway and modulation of the nitric oxide pathway. The review also highlighted AL’s potential in mitigating oxidative stress and its implications in treating cardiovascular diseases, fibrosis, and cancer. Conclusions: The findings suggest that ALA holds significant therapeutic potential, offering antihypertensive, anti-inflammatory, antifibrotic, and anticancer benefits without notable adverse effects, warranting further research to explore its full potential and mechanism of action.

Objective: We aimed to assess the expression and localization of renin-angiotensin system (RAS) receptors in lung tissue and the plasma concentration of related peptides in IPF patients. Materials and Methods: This case–control study involved 19 patients from southern Brazil undergoing lung resection or transplantation. Plasma levels of Angiotensin I, II, A, 1-7, Alamandine were measured via liquid chromatography–tandem mass spectrometry. Lung tissue expression and localization of angiotensin type 1 (AT1), Mas, and Mas-related G-protein-coupled receptor D (MrgD) receptors were evaluated using Western blot and immunohistochemistry. Clinical data and the 6-min walk test were analyzed to correlate receptor expression with lung function and oxygen dependence. Results: IPF patients showed reduced forced vital capacity (FVC) at 49 ± 13% and forced expiratory volume (FEV1) at 51 ± 14%, with a 60% increase in oxygen dependence. Plasma peptide concentrations were similar between the groups, except for Angiotensin I, which was significantly higher in the control group. In IPF lungs, AT1 and Mas receptors were expressed 2.31 and 2.13 times more, respectively, while MrgD expression was lower. Mas receptors were mostly found in bronchiole areas, whereas MrgD was predominant in the lung parenchyma. Conclusions: This study indicates that the RAS operates independently within tissue, in addition to its systemic functions, highlighting distinct differences between tissue and plasma RAS activities. The distinct roles of MrgD and Mas receptors in lung structure and function could be pivotal for new therapies, potentially leading to more effective IPF treatments.

Patients were separated into two groups: (1) non-waiting list (NWL) and (2) waiting list (WL) for the lung transplantation. We found greater levels of the faith and spirituality, in those awaiting transplantation. In the NWL group, higher 'meaning' was associated with higher 'vitality,' 'emotional well-being,' and 'mental health'; higher 'peace' was associated with higher 'mental health.' In the WL group, higher 'peace' was associated with and better 'mental health' and 'emotional well-being.' Regardless of whether patients are lung transplantation candidates or not, spirituality/religiosity may help those with lung diseases cope better with their disease and have better quality of life.

Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1–7 (Ang 1‐7), a product of the renin‐angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. Recent data from our lab reveals that the addition of a non‐radioactive iodine molecule to the tyrosine in position 4 of Ang 1‐7 (iodoAng 1‐7) makes it ~1000‐fold more potent than Ang 1‐7 in competing for the 125I‐Ang 1‐7 binding site (Stoyell‐Conti et al., 2020). Moreover, the addition of the non‐radioactive iodine molecule increases (~4‐fold) iodoAng 1‐7’s ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1‐7 can also compete for the 125I‐Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1‐7 (non‐radioactive iodine isotope) and Ang 1‐7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1‐7, or iodoAng 1‐7 administrated subcutaneously using a 28‐day osmotic mini pump. Systolic BP was measured non‐invasively by the tail‐cuff technique. Cognitive function was assessed by Y‐Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1‐7 prevented the increase in heart rate with age, while Ang 1‐7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1‐7 nor iodoAng 1‐7 administered subcutaneously affected BP nor cognitive function. This study evaluated chronic high‐dose iodotyr(4)angiotensin 1‐7 and angiotensin 1‐7 administration on blood pressure, heart rate and cognitive function in SHR. Iodotyr(4)angiotensin 1‐7 and angiotensin 1‐7 prevented the increase in heart rate over a 27 day period but did not alter blood pressure or performance in a long‐term recognition test or a short‐term spatial memory task.

Hypotension is one of the main characteristics of the systemic inflammation, basically caused by endothelial dysfunction. Studies have shown that the amino acid L‐kynurenine (KYN) causes vasodilation in mammals, leading to hypotensive shock. In hypotensive shock, when activated by the KYN, the voltage‐gated potassium channel encoded by the family KCNQ (Kv7) gene can cause vasodilation. Fructose‐1,6‐bisphosphate (FBP) it is being considered in studies an anti‐inflammatory, antioxidant, immunomodulator, and a modulator of some ion channels (Ca2+, Na+, and K+). We analyzed the effects of KYN and FBP on mean blood pressure (MBP), systolic and diastolic (DBP) blood pressure, and heart rate variability (HRV) in Wistar rats. Results demonstrated that the administration of KYN significant decreased MBP, DBP, and increased HRV. Importantly, the FBP treatment reversed the KYN effects on MBP, DBP, and HRV. Molecular Docking Simulations suggested that KYN and FBP present a very close estimated free energy of binding and the same position into structure of KCNQ4. Our results did demonstrate that FBP blunted the decrease in BP, provoked by KYN. Results raise new hypotheses for future and studies in the treatment of hypotension resulting from inflammation.

Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an \"off-target\" effect of enhancing the enzymatic activity of ACE2 in vitro. To evaluate the pharmacological actions of DIZE in experimental models of PH. PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1α, which was corrected by in vitro DIZE treatment. Our results identify a therapeutic potential of DIZE in PH therapy.

Introduction. Pulmonary fibrosis (PF) is characterized by an accelerated decline in pulmonary function and has limited treatment options. Alamandine (ALA) is a recently described protective peptide of the renin-angiotensin system (RAS) with essential tasks in several conditions. Our group previously demonstrated that ALA is reduced by 365% in the plasma of patients with idiopathic PF, and thus, it is plausible to believe that stimulation of this peptide could represent an important therapeutic target. In this sense, this study investigates the effects of ALA in an experimental model of PF. Materials and Methods. Bleomycin (BLM) was administrated in Wistar rats, and these fibrotic animals were treated with ALA for 14 days. Body weight, histology, respiratory, and hemodynamic parameters were analyzed to study the effects of ALA. Results. ALA treatment attenuated the development of fibrosis (P<0.0001), reduced respiratory system elastance (P<0.0001), and preserved weight gain (P<0.0001) in fibrotic animals without affecting the autonomic control of blood pressure and heart rate. Conclusion. The data from this study demonstrate the potential of ALA to alleviate pulmonary fibrosis and improve respiratory system mechanics in vivo. The promising results encourage more detailed investigations of the potential of ALA as a future and efficient antifibrotic.

Background Spontaneously hypertensive rats (SHRs) show increased cardiac sympathetic activity, which could stimulate cardiomyocyte hypertrophy, cardiac damage, and apoptosis. Norepinephrine (NE)-induced cardiac oxidative stress seems to be involved in SHR cardiac hypertrophy development. Because exercise training (ET) decreases sympathetic activation and oxidative stress, it may alter cardiac hypertrophy in SHR. The aim of this study was to determine, in vivo, whether ET alters cardiac sympathetic modulation on cardiovascular system and whether a correlation exists between cardiac oxidative stress and hypertrophy. Methods Male SHRs (15-weeks old) were divided into sedentary hypertensive (SHR, n = 7) and exercise-trained hypertensive rats (SHR-T, n = 7). Moderate ET was performed on a treadmill (5 days/week, 60 min, 10 weeks). After ET, cardiopulmonary reflex responses were assessed by bolus injections of 5-HT. Autoregressive spectral estimation was performed for systolic arterial pressure (SAP) with oscillatory components quantified as low (LF: 0.2–0.75 Hz) and high (HF: 0.75–4.0 Hz) frequency ranges. Cardiac NE concentration, lipid peroxidation, antioxidant enzymes activities, and total nitrates/nitrites were determined. Results ET reduced mean arterial pressure, SAP variability (SAP var), LF of SAP, and cardiac hypertrophy and increased cardiopulmonary reflex responses. Cardiac lipid peroxidation was decreased in trained SHRs and positively correlated with NE concentrations (r = 0.89, P < 0.01) and heart weight/body weight ratio (r = 0.72, P < 0.01), and inversely correlated with total nitrates/nitrites (r = −0.79, P < 0.01). Moreover, in trained SHR, cardiac total nitrates/nitrites were inversely correlated with NE concentrations (r = −0.82, P < 0.01). Conclusions ET attenuates cardiac sympathetic modulation and cardiac hypertrophy, which were associated with reduced oxidative stress and increased nitric oxide (NO) bioavailability.

This study tested whether a low dose (40% less than the pharmacological dose of 17-β estradiol) would be as effective as the pharmacological dose to improve cardiovascular parameters and decrease cardiac oxidative stress. Female Wistar rats (n=9/group) were divided in three groups: (1) ovariectomized (Ovx), (2) ovariectomized animals treated for 21 days with low dose (LE; 0.2 mg), and (3) high dose (HE; 0.5 mg) 17-β estradiol subcutaneously. Hemodynamic assessment and spectral analysis for evaluation of autonomic nervous system regulation were performed. Myocardial superoxide dismutase (SOD) and catalase (CAT) activities, redox ratio (GSH/GSSG), total radical-trapping antioxidant potential (TRAP), hydrogen peroxide, and superoxide anion concentrations were measured. HE and LE groups exhibited an improvement in hemodynamic function and heart rate variability. These changes were associated with an increase in the TRAP, GSH/GSSG, SOD, and CAT. A decrease in hydrogen peroxide and superoxide anion was also observed in the treated estrogen groups as compared to the Ovx group. Our results indicate that a low dose of estrogen is just as effective as a high dose into promoting cardiovascular function and reducing oxidative stress, thereby supporting the approach of using low dose of estrogen in clinical settings to minimize the risks associated with estrogen therapy.