Modulation of ACE2/Ang1-7/Mas and ACE/AngII/AT1 axes affects anticancer properties of sertraline in MCF-7 breast cancer cells.

The renin-angiotensin system (RAS) is best known for playing a major role in maintaining the physiology of the cardiovascular system. Dysregulation of the RAS pathway has been proposed as a link to some malignancies and contributes to cancer metastasis. Breast cancer is considered as one of the leading causes of cancer death in women and its prevention remains yet a challenge. Elements of RAS are expressed in both normal breast tissue and cancerous cells, signifying the essential role of RAS in breast cancer pathology. Sertraline, a widely used antidepressant, has shown anti-proliferative properties on a variety of malignancies. This study aimed to investigate the effect of sertraline and its combination with agonists and antagonists of RAS (A779, Ang 1-7 and losartan) on viability of MCF-7 cells along with their effect on apoptosis and distribution of cell cycle. Our results indicated that sertraline, losartan and Ang 1-7 significantly decreased cell viability, induced apoptosis and cell cycle arrest. A779 blunted the effect of sertraline on cell viability, ROS generation and cell cycle arrest. Combination treatment of sertraline with losartan as well as Ang 1-7 caused a remarkable decline in cell viability. In conclusion, results of the present study support the anti-cancer properties of sertraline, losartan and Ang 1-7 via induction of apoptosis and cell cycle arrest.

Bibliometric and visual analysis of ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications from 2000 to 2023.

Background: The pathogenesis of diabetes and its microvascular complications are intimately associated with renin angiotensin system dysregulation. Evidence suggests the angiotensin converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis regulates metabolic imbalances, inflammatory responses, reduces oxidative stress, and sustains microvascular integrity, thereby strengthening defences against diabetic conditions. This study aims to conduct a comprehensive analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications over the past two decades, focusing on key contributors, research hotspots, and thematic trends. Methods: This cross-sectional bibliometric analysis of 349 English-language publications was performed using HistCite, VOSviewer, CiteSpace, and Bibliometrix R for visualization and metric analysis. Primary analytical metrics included publication count and keyword trend dynamics. Results: The United States, contributing 105 articles, emerged as the most productive country, with the University of Florida leading institutions with 18 publications. Benter IF was the most prolific author with 14 publications, and Clinical Science was the leading journal with 13 articles. A total of 151 of the 527 author's keywords with two or more occurrences clustered into four major clusters: diabetic microvascular pathogenesis, metabolic systems, type 2 diabetes, and coronavirus infections. Keywords such as "SARS", "ACE2", "coronavirus", "receptor" and "infection" displayed the strongest citation bursts. The thematic evolution in this field expanded from focusing on the renin angiotensin system (2002-2009) to incorporating ACE2 and diabetes metabolism (2010-2016). The latter period (2017-2023) witnessed a significant surge in diabetes research, reflecting the impact of COVID-19 and associated conditions such as diabetic retinopathy and cardiomyopathy. Conclusions: This scientometric study offers a detailed analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications, providing valuable insights for future research directions.

Interaction of Angiotensin-(1-7) with kinins in the kidney circulation: Role of B1 receptors.

Changes in renal hemodynamics impact renal function during physiological and pathological conditions. In this context, renal vascular resistance (RVR) is regulated by components of the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). However, the interaction between these vasoactive peptides on RVR is still poorly understood. Here, we studied the crosstalk between angiotensin-(1-7) and kinins on RVR. The right kidneys of Wistar rats were isolated and perfused in a closed-circuit system. The perfusion pressure and renal perfusate flow were continuously monitored. Ang-(1-7) (1.0-25.0 nM) caused a sustained, dose-dependent reduction of relative RVR (rRVR). This phenomenon was sensitive to 10 nM A-779, a specific Mas receptor (MasR) antagonist. Bradykinin (BK) promoted a sustained and transient reduction in rRVR at 1.25 nM and 125 nM, respectively. The transient effect was abolished by 4 µM des-Arg9-Leu8-bradykinin (DALBK), a specific kinin B1 receptor (B1R) antagonist. Accordingly, des-Arg9-bradykinin (DABK) 1 µM (a B1R agonist) increased rRVR. Interestingly, pre-perfusion of Ang-(1-7) changed the sustained reduction of rRVR triggered by 1.25 nM BK into a transient effect. On the other hand, pre-perfusion of Ang-(1-7) primed and potentiated the DABK response, this mechanism being sensitive to A-779 and DALBK. Binding studies performed with CHO cells stably transfected with MasR, B1R, and kinin B2 receptor (B2R) showed no direct interaction between Ang-(1-7) with B1R or B2R. In conclusion, our findings suggest that Ang-(1-7) differentially modulates kinin's effect on RVR in isolated rat kidneys. These results help to expand the current knowledge regarding the crosstalk between the RAS and KKS complex network in RVR.

Adipose tissue plasticity mediated by the counterregulatory axis of the renin-angiotensin system: Role of Mas and MrgD receptors.

The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

The renin-angiotensin system (RAS) is an important cascade of enzymes and peptides that regulates blood pressure, volume, and electrolytes. Within this complex system of reactions, its counter-regulatory axis has attracted attention, which has been associated with the pathophysiology of inflammatory and fibrotic diseases. This review article analyzes the impact of different components of the counter-regulatory axis of the RAS on different pathologies. Of these peptides, Angiotensin-(1-7), angiotensin-(1-9) and alamandine have been evaluated in a wide variety of in vitro and in vivo studies, where not only they counteract the actions of the classical axis, but also exhibit independent anti-inflammatory and fibrotic actions when binding to specific receptors, mainly in heart, kidney, and lung. Other functional peptides are also addressed, which despite no reports associated with inflammation and fibrosis to date were found, they could represent a potential target of study. Furthermore, the association of agonists of the counter-regulatory axis is analyzed, highlighting their contribution to the modulation of the inflammatory response counteracting the development of fibrotic events. This article shows an overview of the importance of the RAS in the resolution of inflammatory and fibrotic diseases, offering an understanding of the individual components as potential treatments.

Unraveling the crosstalk between renin-angiotensin system receptors.

The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.

The Mas agonist CGEN-856S prevents Ang II induced cardiomyocyte hypertrophy via nitric oxide production.

With the previous knowledge of the cardioprotective effects of the Angiotensin-(1-7) axis, a agonist of Mas receptor has been described, the CGEN-856S. This peptide is more stable than Ang-(1-7), and has a low binding affinity to Angiotensin II receptors. Although the cardioprotective effects of CGEN-856S were previously shown in vivo, the mechanisms behind its effects are still unknown. Here, we employed a combination of molecular biology, confocal microscopy, and genetically modified mouse with Mas deletion to investigate the CGEN-856S protective signaling in cardiomyocytes. In isolated adult ventricular myocytes, CGEN-856S induced an increase in nitric oxide (NO) production which was absent in cells from Mas knockout mice. Using western blot, we observed a significant increase in phosphorylation of AKT after treatment with CGEN-856S. In addition, CGEN-856S prevented the Ang II induced hypertrophy and the nuclear translocation of GRK5 in a culture model of rat neonatal cardiomyocytes. Blockage of Mas receptor and inhibition of the NO synthase abolished the effects of CGEN-856S on Ang II treated cardiomyocytes. In conclusion, we show that CGEN-856S acting via receptor Mas induces NO raise to block Ang II induced cardiomyocyte hypertrophy. These results indicate that CGEN-856S acts very similarly to Ang-(1-7) in cardiac myocytes, highlighting its therapeutic potential for treating cardiovascular diseases.

Co-activation of Mas and pGCA receptors suppresses Endothelin-1-induced endothelial dysfunction via nitric oxide/cGMP system.

BACKGROUND: The aortic endothelium is crucial in preserving vascular tone through endothelium-derived vasodilators and vasoconstrictors. Dysfunction in the endothelium is an early indicator of cardiovascular diseases. Our study explores the therapeutic potential of a dual-acting peptide (DAP) to co-activate Mas and pGCA receptors and restore the balance between vasodilators and vasoconstrictors on endothelial dysfunction in DOCA-salt-induced hypertensive rats. METHODS: DOCA-salt was administered to male wistar rats to induce hypertension, and various parameters, including blood pressure (BP), water intake and body weight were monitored. DAP, Ang1-7, BNP, and losartan were administered to hypertensive rats for three weeks. Histological analysis and isometric tension studies were carried out to assess endothelial function. In addition to this, we used primary aortic endothelial cells for detailed mechanistic investigations. RESULTS: DOCA-salt administration significantly elevated systolic, diastolic, mean arterial BP, and water intake whereas, downregulated the gene expression of Mas and pGCA receptors. However, DAP co-administration attenuated BP increase, upregulated the gene expression of Mas and pGCA receptors, normalized serum and urinary parameters, and effectively reduced fibrosis, inflammation, and vascular calcification. Notably, DAP outperformed the standard drug, Losartan. Our findings indicate that DAP restores aortic function by balancing the NO and ET1-induced pathways. CONCLUSION: Co-activating Mas and pGCA receptors with DAP mitigates vascular damage and enhances endothelial function, emphasizing its potential to maintain a delicate balance between vasodilatory NO and vasoconstrictor ET1 in endothelial dysfunction.

BIO101 stimulates myoblast differentiation and improves muscle function in adult and old mice.

BACKGROUND: Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse. Age-related imbalance of protein synthesis and degradation, mainly regulated by AKT/mTOR pathway, leads to progressive loss of muscle mass. Maintenance of anabolic and regenerative capacities of skeletal muscles may be regarded as a therapeutic option for sarcopenia and other muscle wasting diseases. Our previous studies have demonstrated that BIO101, a pharmaceutical grade 20-hydroxyecdysone, increases protein synthesis through the activation of MAS receptor involved in the protective arm of renin-angiotensin-aldosterone system. The purpose of the present study was to assess the anabolic and pro-differentiating properties of BIO101 on C2C12 muscle cells in vitro and to investigate its effects on adult and old mice models in vivo. METHODS: The effects of BIO101 on C2C12 differentiation were assessed using myogenic transcription factors and protein expression of major kinases of AKT/mTOR pathway by Western blot. The in vivo effects of BIO101 have been investigated in BIO101 orally-treated (50 mg/kg/day) adult mice (3 months) for 28 days. To demonstrate potential beneficial effect of BIO101 treatment in a sarcopenic mouse model, we use orally treated 22-month-old C57Bl6/J mice, for 14 weeks with vehicle or BIO101. Mice body and muscle weight were recorded. Physical performances were assessed using running capacity and muscle contractility tests. RESULTS: Anabolic properties of BIO101 were confirmed by the rapid activation of AKT/mTOR, leading to an increase of C2C12 myotubes diameters (+26%, P < 0.001). Pro-differentiating effects of BIO101 on C2C12 myoblasts were revealed by increased expression of muscle-specific differentiation transcription factors (MyoD, myogenin), resulting in increased fusion index and number of nuclei per myotube (+39% and +53%, respectively, at day 6). These effects of BIO101 were like those of angiotensin (1-7) and were abolished with the use of A779, a MAS receptor specific antagonist. Chronic BIO101 oral treatment induced AKT/mTOR activation and anabolic effects accompanied with improved physical performances in adult and old animals (maximal running distance and maximal running velocity). CONCLUSIONS: Our data suggest beneficial anabolic and pro-differentiating effects of BIO101 rendering BIO101 a potent drug candidate for treating sarcopenia and possibly other muscle wasting disorders.

Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin.

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin's (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups' cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST's normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST's potential as a promising treatment intervention, inviting further neurological research implications.

The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760.

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN). RESULTS: Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect. CONCLUSIONS: Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

Angiotensin(1-7) attenuates tooth movement and regulates alveolar bone response during orthodontic force application in experimental animal model.

BACKGROUND: Renin-angiotensin system and its ACE2/Ang(1-7)/Mas receptor axis regulates skeletal response to multiple physiological and pathological conditions. Recent research suggested a vital role of Ang(1-7) in regulating alveolar bone metabolism and remodeling. In this context, this study evaluated the effects of the Ang(1-7)/Mas receptor axis on orthodontic tooth movement (OTM) and the alveolar bone response to mechanical load. METHODS: A coil spring was placed between the right maxillary first molar and the anterior tooth of Wistar rats to apply bidirectional mechanical force. Ang(1-7) with or without a specific Mas receptor antagonist (A779) was infused using subcutaneous osmotic pumps (200 and 400 ng/kg/min: respectively). Animals were killed after 5 and 14 days from the OTM procedure after the clinical evaluation of tooth movement and mobility. Morphometric analysis of alveolar bone structure was conducted using micro-CT and the histological picture was evaluated after H&E staining. Moreover, collagen fiber distribution was assessed using Picro-Sirius red stain. In addition, bone samples were collected from the pressure and tension sites around the anterior tooth for gene expression analysis. RESULTS: Ang(1-7) infusion suppressed the tooth movement and mobility after 14 days of the orthodontic force application. Additionally, Ang(1-7) infusion preserved the morphometric and histological structure of the alveolar bone at pressure and tension sides. These effects were abolished by adding A779 infusion. Collagen fiber distribution was dysregulated mainly by the A779 Mas receptor blockage. Ang(1-7) affected the bone formation, remodeling- and vascularity-related genes in the pressure and tension sides, suggesting a prominent suppression of osteoclastogenesis. Ang(1-7) also improved osteoblasts-related genes on the tension side, whereas the osteoclasts-related genes were augmented by A779 on the pressure side. CONCLUSION: Collectively, the activation of Ang(1-7)/Mas receptor axis appears to hinder tooth movement and regulates alveolar bone remodeling in response to mechanical force.

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-ß-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.

PDZK1 improves ventricular remodeling in hypertensive rats by regulating the stability of the Mas receptor.

Ventricular remodeling is one of the main causes of mortality from heart failure due to hypertension. Exploring its mechanism and finding therapeutic targets have become urgent scientific problems to be solved. A number of studies have shown that Mas, as an Ang-(1-7) specific receptor, was significantly reduced in myocardial tissue of rats undergoing hypertensive ventricular remodeling. It has been reported that Mas receptor levels are significantly downregulated in myocardium undergoing ventricular remodeling, but studies focused on intracellular and post-translational modifications of Mas are lacking. The results of this research are as follows: (1) PDZK1 interacts with the carboxyl terminus of Mas through its PDZ1 domain; (2) the expression of PDZK1 and Mas is decreased in rats undergoing hypertensive ventricular remodeling, and PDZK1 upregulation can ameliorate hypertensive myocardial fibrosis and myocardial hypertrophy; (3) PDZK1 enhances the stability of Mas protein through the proteasome pathway, and the proteasome inhibitor MG132 promotes hypertensive ventricular remodeling. PDZK1 improves ventricular remodeling in hypertensive rats by regulating Mas receptor stability. This study provides a scientific basis for the prevention and treatment of ventricular remodeling.

From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection.

Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.

The Renin Angiotensin System as a Therapeutic Target in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major public health problem, with limited pharmacological options available beyond symptomatic relief. The renin angiotensin system (RAS) is primarily known as a systemic endocrine regulatory system, with major roles controlling blood pressure and fluid homeostasis. Drugs that target the RAS are used to treat hypertension, heart failure and kidney disorders. They have now been used chronically by millions of people and have a favorable safety profile. In addition to the systemic RAS, it is now appreciated that many different organ systems, including the brain, have their own local RAS. The major ligand of the classic RAS, Angiotensin II (Ang II) acts predominantly through the Ang II Type 1 receptor (AT1R), leading to vasoconstriction, inflammation, and heightened oxidative stress. These processes can exacerbate brain injuries. Ang II receptor blockers (ARBs) are AT1R antagonists. They have been shown in several preclinical studies to enhance recovery from TBI in rodents through improvements in molecular, cellular and behavioral correlates of injury. ARBs are now under consideration for clinical trials in TBI. Several different RAS peptides that signal through receptors distinct from the AT1R, are also potential therapeutic targets for TBI. The counter regulatory RAS pathway has actions that oppose those stimulated by AT1R signaling. This alternative pathway has many beneficial effects on cells in the central nervous system, bringing about vasodilation, and having anti-inflammatory and anti-oxidative stress actions. Stimulation of this pathway also has potential therapeutic value for the treatment of TBI. This comprehensive review will provide an overview of the various components of the RAS, with a focus on their direct relevance to TBI pathology. It will explore different therapeutic agents that modulate this system and assess their potential efficacy in treating TBI patients.

Association of the ACE2-Angiotensin1-7-Mas axis with lung damage caused by cigarette smoke exposure: a systematic review.

Through the Mas receptor, angiotensin-(1-7) [Ang-(1-7)] has been shown to have a key role in the development of lung inflammation. This systematic review (SR) sought to identify the relationship between lung damage brought on by exposure to cigarette smoke (CS) and the ACE2-Ang-(1-7)-Mas pathway. In this investigation, relevant keywords were used to search PubMed (MEDLINE), Scopus (Elsevier), and Institute for Scientific Information (ISI) Web of Science up to December 2022. Nine studies were chosen because they satisfied the inclusion/exclusion criteria. The majority of research concluded that exposure to CS increased the risk of lung damage. Smoking cigarettes is the main cause of COPD because it causes massive amounts of reactive oxygen and nitrogen species to enter the lungs, which stimulate the production of inflammatory cytokines like IL-1 ß, IL-6, and TNF-α, as well as the invasion of inflammatory cells like neutrophils and macrophages. These findings support the renin-angiotensin system's (RAS) involvement in the pathophysiology of smoking-induced damage. Additionally, via stimulating pro-inflammatory mediators, aberrant RAS activity has been linked to lung damage. Lung inflammation's etiology has been shown to be significantly influenced by the protective known RAS arm ACE2-Ang-(1-7)-Mas. In conclusion, these are important for informing policymakers to pass legislation limiting the use of smoking and other tobacco to prevent their harmful effects.

Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice.

Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1-7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1-7)/MAS receptor pathway and resulting in antidepressant-like effects.

Novel Potential Targets for Function-Promoting Therapies: Orphan Nuclear Receptors, Anti-inflammatory Drugs, Troponin Activators, Mas Receptor Agonists, and Urolithin A.

In recent years, several new classes of therapies have been investigated with their potential for restoring or improving physical functioning in older adults. These have included Mas receptor agonists, regulators of mitophagy, skeletal muscle troponin activators, anti-inflammatory compounds, and targets of orphan nuclear receptors. The present article summarizes recent developments of the function-promoting effects of these exciting new compounds and shares relevant preclinical and clinical data related to their safety and efficacy. The development of novel compounds in this area is expanding and likely will need the advent of a new treatment paradigm for age-associated mobility loss and disability.

ACE2/ANG-(1-7)/Mas receptor axis activation prevents inflammation and improves cognitive functions in streptozotocin induced rat model of Alzheimer's disease-like phenotypes.

Activation of the renin-angiotensin system (RAS), by Angiotensin converting enzyme/Angiotensin II/Angiotensin receptor-1 (ACE/Ang II/AT1 R) axis elicits amyloid deposition and cognitive impairment. Furthermore, ACE2 induced release of Ang-(1-7) binds with the Mas receptor and autoinhibits ACE/Ang II/AT1 axis activation. Inhibition of ACE by perindopril has been reported to improve memory in preclinical settings. However, the functional significance and mechanism by which ACE2/Mas receptor regulate cognitive functions and amyloid pathology is not known. The present study is aimed to determine the role of ACE2/Ang-(1-7)/Mas receptor axis in STZ induced rat model of Alzheimer's disease (AD). We have used pharmacological, biochemical and behavioural approaches to identify the role of ACE2/Ang-(1-7)/Mas receptor axis activation on AD-like pathology in both in vitro and invivo models. STZ treatment enhances ROS formation, inflammation markers and NFκB/p65 levels which are associated with reduced ACE2/Mas receptor levels, acetylcholine activity and mitochondrial membrane potential in N2A cells. DIZE mediated ACE2/Ang-(1-7)/Mas receptor axis activation resulted in reduced ROS generation, astrogliosis, NFκB level and inflammatory molecules and improved mitochondrial functions along with Ca2+ influx in STZ treated N2A cells. Interestingly, DIZE induced activation of ACE2/Mas receptor significantly restored acetylcholine levels and reduced amyloid-beta and phospho-tau deposition in cortex and hippocampus that resulted in improved cognitive function in STZ induced rat model of AD-like phenotypes. Our data indicate that ACE2/Mas receptor activation is sufficient to prevented cognitive impairment and progression of amyloid pathology in STZ induced rat model of AD-like phenotypes. These findings suggest the potential role of ACE2/Ang-(1-7)/Mas axis in AD pathophysiology by regulating inflammation cognitive functions.