Renal fibrosis is a fundamental pathological change in the progression of various chronic kidney diseases to the end stage of renal disease. The Hippo signaling pathway is an evolutionary highly conserved signaling pathway that is involved in the regulation of organ size, tissue regeneration, and human reproduction and development. Currently, many studies have shown that it is closely associated with renal diseases, such as, renal fibrosis, diabetic nephropathy, and renal cancer. Here, we review the current researches on the effect of Hippo signaling pathway on renal fibrosis, which provides new ideas and theoretical basis for clinical therapeutics of renal fibrosis.

There is a local renin-angiotensin system (RAS) in the ovary, which is involved in regulating many important physiological processes, but the specific mechanism remains unclear. Polycystic ovarian syndrome (PCOS) is the most frequently reported non-iatrogenic condition with abnormal RAS expression, characterized by overweight or obesity and insulin resistance (IR), both of which are significantly correlated with many long-term complications. These conditions are closely linked to circulatory or local RAS, serving as potential common regulatory nodes. The present study analyzed single-cell RNA sequencing (scRNA-seq) data from mouse ovaries during the reproductive period to obtain the expression levels and location information of RAS components in all cell clusters. It further analyzed the cyclical fluctuations of RAS and the differential gene sets during the estrous cycle. Protein-protein interaction analysis predicted the most closely interacting pathway with RAS, and preliminary evidence of crosstalk between angiotensin II (AngII) and the insulin signaling pathway was identified in the scRNA-seq data. A PCOS mouse model was constructed, replicating clinical reproductive and metabolic complications, and the crosstalk between AngII and IRS1/PI3K/AKT was verified. In conclusion, this study revealed the dynamic changes of the ovarian local RAS at the cellular level during the estrous cycle, and described the role of RAS in regulating ovarian function from a single-cell perspective. It also provided evidence that IR, caused by the crosstalk between AngII and IRS1/PI3K/AKT pathways, may be a potential underlying mechanism of PCOS.

Emerging evidence suggests that the renin-angiotensin system plays an important role in the pathogenesis of inflammatory bowel disease, but few studies have directly assessed the therapeutic effect of renin inhibitors on colitis development.

Experimental colitis was induced in wild-type C57BL/6 mice and renin transgenic (RenTg) mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Following intrarectal TNBS instillation, the mice were treated with SPH3127 (sitokiren), a small-molecule renin inhibitor, twice a day by intraperitoneal injection or oral gavage. The therapeutic effect of SPH3127 was evaluated by assessing clinical symptoms, histological injuries, and colonic mucosal inflammatory parameters in these mice.

SPH3127 treatment by either delivery route markedly attenuated body weight loss, reduced clinical severity, alleviated colon mucosal ulceration in both C57BL/6 and RenTg mice, and prevented animal death in the case of RenTg mice. SPH3127 treatment blocked the local induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ, IL-17) and promoted the production of anti-inflammatory cytokine IL-10 in the colon. Fluorescence-activated cell sorting analysis revealed that SPH3127 substantially diminished the accumulation of TH1 and TH17 cells in the colonic mucosa and confirmed that SPH3127-induced IL-10 production from mucosal CD25+ T cells in the mice.

These results demonstrate that SPH3127 is able to effectively block colitis development in mouse experimental colitis models. Its anti-colitogenic activity is achieved at least in part by suppressing mucosal TH1 and TH17 activation while promoting IL-10 production from mucosal CD25+ T cells, thus forming an anti-inflammatory environment in the colonic mucosa.

Venezuelan equine encephalitis virus (VEEV) is an alphavirus in the family Togaviridae, transmitted by a mosquito bite and is highly infectious in aerosol form. Inflammation plays a role of antiviral response as well as development of lethal encephalitis. Infection through a mosquito bite is biphasic, beginning with an inflammatory process and viral replication in different organs with subsequent infiltration to the central nervous system (CNS), inducing encephalitis. The direct route is through inhalation of aerosols containing the virus with direct brain infection through the olfactory nerve. Significant damage is due to exacerbated inflammation in the host. Angiotensin II (Ang II) is a molecule with high pro-inflammatory capacity, which has been found to be upregulated in the brain of VEEV-infected rats, suggesting its role in the pathogenesis of this disease. Limited information regarding the association of Ang II expression with VEEV brain infection has been reported. The aim of this review is to highlight published reports indicating a possible association between Ang II expression and VEEV-induced encephalitis. Several studies reflect a possible expression and function of Ang II during VEEV infection. Factors such as the relationship of Ang II with proteins involved in viral replication and entry into the cell (furin, Rab5, Rab7), activation of protein kinase C (necessary for the phosphorylation of VEEV), presence of microRNAs related to viral biology, increased permeability of the blood-brain barrier, and use of transcription pathways common to Ang II and VEEV, may conceivable an association of Ang II with the pathogenesis of VEEV encephalitis.

The interaction between vitamin D and the immune system is perhaps the most well recognised extraskeletal facet of vitamin D, encompassing early studies of therapy for TB and leprosy through to more recent links with autoimmune disease. However, the spotlight on vitamin D and immune function has been particularly intense in the last five years following the COVID-19 pandemic. This was due, in part, to the many association studies of vitamin D status and COVID-19 infection and disease prognosis, as well as the smaller number of clinical trials of vitamin D supplementation. However, a potential role for vitamin D in COVID-19 also stemmed from the basic biology of vitamin D that provides a plausible mechanistic rationale for beneficial effects of vitamin D for improved immune health in the setting of respiratory infection. The aim of this review is to summarise the different strands of mechanistic evidence supporting a beneficial effect of vitamin D in COVID-19, how this was modified during the pandemic itself, and the potential new aspects of vitamin D and immune function that are likely to arise in the near future. Key topics that feature in this review are: antibacterial versus antiviral innate immune responses to 1,25-dihydroxyvitamin D (1,25(OH)2D); the function of immune 1α-hydroxylase (CYP27B1) activity and metabolism of 25-hydroxyvitamin D (25(OH)D) beyond antigen-presenting cells; advances in immune cell target gene responses to 1,25-dihydroxyvitamin D (notably changes in metabolic profile). Whilst much of the interest during the COVID-19 era has focused on vitamin D and public health, the continued evolution of our understanding of how vitamin D interacts with different components of the immune system continues to support a beneficial role for vitamin D in immune health.

Angiotensin-Converting Enzyme (ACE) plays a pivotal role in the renin-angiotensin system, modulating blood pressure and electrolyte homeostasis by deactivating bradykinin and activating angiotensin II. Metabolites from Senecio nutans (1 and 3), a plant indigenous to the Andean region of the Atacama Desert, and their respective oximes, 2 and 4, were subjected to molecular docking analysis, employing six ACE crystal structures. ACE activity assays revealed that oximes exhibited superior inhibitory effects compared to metabolites. Among the compounds investigated, 2 emerged as the most potent ACE inhibitor (2 = 11.5 μM and 4 = 13.4 μM). The vascular contractile response to Angiotensin I showed significant (p < 0.05) reductions in Ang I contraction with 2, 3, and 4 (97 ± 6%, 81 ± 6%, 81 ± 3% compared to control), while 1 exhibited no such effect. These results reinforce the potential of 2 as a promising ACE inhibitor and highlight its impact on vascular contractility. As such, it is a promising candidate for ACE inhibition and hypertension treatment.

Head and neck tumors represent a prevalent category of oral and maxillofacial malignancies, posing significant therapeutic and prognostic challenges due to their complex anatomical structure, tumor heterogeneity, and resistance to conventional therapies. Recent studies have highlighted the strong association between tumor progression and neoangiogenesis, with the angiopoietin (ANG) family playing a central role in this process. Comprising ANG1, ANG2, ANG3, and ANG4, these factors regulate multiple signaling pathways that promote cellular growth, differentiation, and proliferation, thereby driving angiogenesis and accelerating tumor growth and metastasis. Therefore, a comprehensive investigation of the ANG family's role in head and neck tumors may offer critical insights into tumorigenesis mechanisms and unveil novel therapeutic targets. Such research has the potential to improve treatment outcomes and enhance the quality of life for patients.

Background/Objectives: Disrupted intracellular calcium (Ca2+i) regulation and renin-angiotensin system (RAS) activation are pathogenetic factors in diabetic cardiomyopathy, a major complication of type 1 (T1D) and type 2 (T2D) diabetes. This study explored their potential link in diabetic rat hearts. Methods: Experiments were conducted on T1D and T2D Sprague-Dawley rats induced by streptozotocin and fructose-rich diet, respectively. In T1D, rats were treated with Enalapril (Ena) or Losartan (Los) for six weeks, whereas T2D animals received high-dose (HD) or low-dose (LD) Ena for 8 weeks. Heart function was assessed via echocardiography, Ca2+i transients by Indo-1 fluorometry in Langendorff-perfused hearts, and key Ca2+i cycling proteins by Western blot. Data: mean ± SD. Results: Diabetic hearts exhibited reduced contractile performance that was improved by RAS inhibition both in vivo (ejection fraction (%): T1D model: Control: 79 ± 7, T1D: 54 ± 11, T1D + Ena: 65 ± 10, T1D + Los: 69 ± 10, n = 18, 18, 15, 10; T2D model: Control: 73 ± 8, T2D: 52 ± 6, T2D + LDEna: 62 ± 8, T2D + HDEna: 76 ± 8, n = 9, 8, 6, 7) and ex vivo (+dPressure/dtmax (mmHg/s): T1D model: Control: 2532 ± 341, T1D: 2192 ± 208, T1D + Ena: 2523 ± 485, T1D + Los: 2643 ± 455; T2D model: Control: 2514 ± 197, T2D: 1930 ± 291, T2D + LDEna: 2311 ± 289, T2D + HDEna: 2614 ± 268). Analysis of Ca2+i transients showed impaired Ca2+i release and removal dynamics and increased diastolic Ca2+i levels in both models that were restored by Ena and Los treatments. We observed a decrease in sarcoendoplasmic reticulum Ca2+-ATPase2a (SERCA2a) expression, accompanied by a compensatory increase in 16Ser-phosphorylated phospholamban (P-PLB) in T2D that was prevented by both LD and HD Ena (expression level (% of Control): SERCA2a: T2D: 36 ± 32, T2D + LDEna: 112 ± 32, T2D + HDEna: 106 ± 30; P-PLB: T2D: 557 ± 156, T2D + LDEna: 129 ± 38, T2D + HDEna: 108 ± 42; n = 4, 4, 4). Conclusions: The study highlights the critical role of RAS activation, most likely occurring at the tissue level, in disrupting Ca2+i homeostasis in diabetic cardiomyopathy. RAS inhibition with Ena or Los mitigates these disturbances independent of blood pressure effects, underlining their importance in managing diabetic heart failure.

The renin-angiotensin system (RAS) plays a pivotal role in regulating blood volume, systemic vascular resistance, and electrolyte balance, serving as a key component of cardiovascular health. Recent findings highlight the role of angiotensin II (Ang II) in inducing autophagy through angiotensin II receptor type 1 (AT1R). Autophagy, a process of self-degradation and turnover of cellular components, is a homeostatic response that eliminates superfluous materials. Abnormal autophagy promotes cardiomyocyte loss and is critical in hypertrophy and heart failure progression. The RAS's non-canonical axis, which includes the angiotensin 1-9 peptide [Ang-(1-9)], has an anti-hypertrophic effect in cardiomyocytes via an unknown mechanism. In the present study, we aimed to elucidate the effect of Ang-(1-9) on cardiomyocyte autophagy.

We isolated and cultured neonatal ventricular cardiomyocytes and then co-treated them with Ang-(1-9) in the presence of chloroquine (CQ), Ang-II, and chemical inhibitors of different signaling pathways. After treatment, total RNA and protein extracts were obtained to analyze the abundance of different autophagy markers. Likewise, cells were fixed, and autophagy was analyzed through epifluorescence microscopy.

Our findings show that CQ leads to a reduction in autophagy markers, such as microtubule-associated protein 1 light chain 3-II (LC3-II) and total LC3, suggesting Ang-(1-9)'s regulatory role in basal autophagy levels. Furthermore, Ang-(1-9) opposes Ang-II-induced autophagy and induces the phosphorylation of the S234 residue of Beclin-1 (BCN1) via an angiotensin II receptor type 2 (AT2R)/Akt-dependent pathway.

This reduction of Ang-II-induced autophagy by Ang-(1-9) unveils a novel aspect of its action, potentially contributing to its cardioprotective effects.

This study aimed to investigate the role of let-7a-5p in the pathogenesis of essential hypertension (EH) and its correlation with the renin-angiotensin-aldosterone system (RAAS) biomarkers. Ninety-eight EH patients and 24 healthy controls (HC) enrolled in the study were assayed for the relative expression of let-7a-5p in plasma by quantitative real-time polymerase chain reaction (Q-PCR), and biomarkers of the RAAS system, including angiotensin-converting enzyme 2 (ACE2), Ang (1-7), MAS1, angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R), were determined by enzyme-linked immunosorbent assay (ELISA) The expression levels of the biomarkers of RAAS system were determined. The results showed that the expression levels of let-7a-5p in the plasma of EH patients were remarkably higher than those of HC. The prediction model of combined let-7a-5p showed high accuracy by constructing a subject operating characteristic (ROC) curve with an area under the curve (AUC) of 0.885, and the reliability of the model was further verified by the Hosmer-Lemeshow (H-L) goodness-of-fit test, the Model Calibration Curve, and the Decision Curve Analysis. Spearman correlation analysis revealed that the expression of let-7a-5p was positively correlated with ACE (r = 0.352, p < 0.001), and mediation analysis indicated that ACE partially mediated between let-7a-5p and the development of hypertension. The present study concludes with the potential of let-7a-5p as a companion diagnostic biomarker for EH. It suggests that there may be a complex regulatory mechanism between it and specific RAAS biomarkers, which provides a new perspective on the pathogenesis and diagnosis of EH.

Background/Objectives: The SARS-CoV-2's high mutations and replication rates contribute to its high infectivity and resistance to current vaccinations and treatments. The primary cause of resistance to most current treatments aligns within the coding regions for the spike S protein of SARS-CoV-2 that has mutated. As a potential novel immunotherapy, we generated a novel fusion protein composed of a soluble ACE2 (sACE2) linked to llama-derived anti-CD16 that targets different variants of spike proteins and enhances natural killer cells to target infected cells. Methods: Here, we generated a novel sACE2-AntiCD16VHH fusion protein using a Gly4Ser linker, synthesized and cloned into the pLVX-EF1alpha-IRES-Puro vector, and further expressed in ExpiCHO-S cells and purified using Ni+NTA chromatography. Results: The fusion protein significantly blocked SARS-CoV-2 alpha, beta, delta, gamma, and omicron S-proteins binding and activating angiotensin-converting enzyme receptor-2 (ACE2) on ACE2-expressing RAW-Blue macrophage cells and the secretion of several key inflammatory cytokines, G-CSF, MIP-1A, and MCP-1, implicated in the cytokine release storm (CRS). The sACE2-Anti-CD16VHH fusion protein also bridged NK cells to ACE2-expressing human lung carcinoma A549 cells and significantly activated NK-dependent cytotoxicity. Conclusions: The findings show that a VHH directed against CD16 could be an excellent candidate to be linked to soluble ACE2 to generate a bi-specific molecule (sACE2-AntiCD16VHH) suitable for bridging effector cells and infected target cells to inhibit SARS-CoV-2 variant spike proteins binding to the ACE2 receptor in the RAW-Blue cell line and pro-inflammatory cytokines and to activate natural killer cell cytotoxicity.

The renin-angiotensin system (RAS), composed mainly of renin, angiotensin, and aldosterone, is a key endocrine pathway involved in cardiovascular activity regulation. Under physiological conditions, the RAS plays a vital role in water and salt metabolism, blood pressure regulation, and electrolyte balance. Angiotensin II (Ang II) is the most important active component of the RAS, and its receptors are concentrated in vascular, pulmonary, cardiac, and renal tissues in vivo. Moreover, Ang II is closely associated with the development of vascular lesions. Ang II expression is closely associated with atherosclerosis, aortic aneurysm/dissection, ischemic stroke, hypertension, pulmonary hypertension, and type 2 diabetes mellitus. Given the significant pathophysiological role of Ang II in vascular diseases and the availability of advanced detection methods, Ang II holds promise as a reliable biomarker and therapeutic target in clinical settings. This review summarizes the mechanisms through which Ang II contributes to different vascular diseases and discusses its potential application as a biomarker for disease diagnosis.

Cardiovascular-kidney-metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental exposures or mechanisms, are used to explore the developmental origins of CKMS. However, no single model can fully replicate all aspects of CKMS or its clinical stages, limiting the advancement of preventive and therapeutic strategies. This review aims to assist researchers by comparing the strengths and limitations of common animal models used in CKMS programming studies and highlighting key considerations for selecting suitable models.

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

Elevated renin has been shown to predict poor response to standard vasoactive therapies and is associated with poor outcomes in adults. Similarly, elevated renin was associated with mortality in children with septic shock. Renin concentration profiles after pediatric cardiac surgery are unknown. The purpose of this study was to characterize renin kinetics after pediatric cardiac surgery.

Single-center retrospective study of infants who underwent cardiac surgery with cardiopulmonary bypass (CPB) utilizing serum samples obtained in the perioperative period to measure plasma renin concentrations (pg/mL). Time points included pre-bypass and 1, 4, and 24 h after initiation of CPB.

Fifty patients (65% male) with a median age 5 months (interquartile range (IQR) 3.5, 6.5) were included. Renin concentrations peaked 4 h after CPB. There was a significant difference in preoperative and 4 h post-CPB renin concentration (4 h post-CPB vs preoperative: mean difference 100.6, 95% confidence interval (CI) 48.9-152.4, P < .001). Median renin concentration at 24 h after CPB was lower than the preoperative baseline.

We describe renin kinetics in infants after CPB. Future studies based on these data can now be performed to evaluate the associations of elevated renin concentrations with adverse outcomes.

Cancer is a complex disease characterized by uncontrolled cell proliferation at various levels, leading to tumor growth and spread. This review focuses on the role of ion homeostasis in cancer progression. It describes a model of ion-mediated regulation in both normal and cancerous cell proliferation. The main function of this system is to maintain the optimal number of cells in the body by regulating intra- and extracellular ion content. The review discusses the key points of ion regulation and their impact on tumor growth and spread during cancer development. It explains that normal levels of sodium, potassium, calcium, chloride, and hydrogen ions are regulated at different levels. Damage to ion transport mechanisms during carcinogenesis can lead to an increase in sodium cations and water content in cells, disrupting the balance of calcium and hydrogen ions. This, in turn, can lead to chromatin compaction reduction, gene overexpression, and instability at the epigenetic and genomic levels, resulting in increased cell proliferation and mutagenesis. Restoring normal ion balance can reduce the proliferative potential of both normal and tumor cell populations. The proposed model of systemic ionic regulation of proliferation aims to reconcile diverse data related to cell mitotic activity in various physiological conditions and explain tumor growth. Understanding the mechanisms behind pathological cell proliferation is important for developing new approaches to control ion homeostasis in the body, potentially leading to more effective cancer treatment and prevention.

The brain's Renin-Angiotensin System plays an important role in the modulation of mental state. Previously we demonstrated that activated angiotensin (Ang) converting enzyme (ACE) 2, which converts Ang II into Ang (1-7), or the intracerebroventricular administration of Ang (1-7) produced an antidepressant-like effect in mice via Mas receptors (MasR). Since the ACE inhibitor Captopril (Cap) increases Ang (1-7) in the brain, it remains unknown whether Cap affects the depressive-like behavior of olfactory bulbectomized (OBX) mice, an animal model of depression. We tested the effect of Cap on the depressive-like behavior of these mice in the tail-suspension test, quantified ACE2, p-AMP activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF) using western blots, and examined the changes in Ang (1-7) level, neurogenesis, and in the expression of ACE2 and MasR on various cell types in the hippocampus using immunohistochemistry. While OBX mice exhibited a depressive-like behavior in the tail-suspension test, as well as a reduction in ACE2, Ang (1-7), p-AMPK, BDNF, and hippocampal neurogenesis, these changes were prevented by Cap administration. The intracerebroventricular administration of Ang (1-7) improved the OBX-induced depressive-like behavior. Except for the changes in ACE2 and Ang (1-7), the effects of Cap were inhibited by the coadministration of A779 (MasR inhibitor) or Compound-C (AMPK inhibitor). ACE2 localized to all cell types, while MasR localized to microglia and neurons. Our results suggest that Cap may act on ACE2-positive cells in the hippocampus to increase ACE2 expression level, thereby enhancing signaling in the ACE2/Ang (1-7)/MasR/AMPK/BDNF pathway and producing antidepressant-like effects.

In the past decade, microplastics (MPs) have drawn significant attention as widespread environmental contaminants, with research increasingly highlighting their harmful effects on respiratory health in aquatic and terrestrial organisms. Findings revealed microplastics in human lung tissues, raising concerns about their potential role in damaging lung tissue integrity and contributing to pulmonary fibrosis-a chronic inflammatory condition characterized by scarring of lung epithelial tissues due to accumulated extracellular matrix, triggered by factors such as alcohol, pathogens, genetic mutations, and environmental pollutants.

In this review, we explore both well-studied and lesser-studied mechanisms and signaling pathways, aiming to shed light on how microplastics might act as mediators that activate distinct, often overlooked signaling cascades.

This review searched PubMed and Google Scholar using keywords like "plastic," "microplastic," "lung fibrosis," "pulmonary system," "exposure route," and "signaling pathways," combined with "OR" and "AND" in singular and plural forms.

These pathways could not only induce lung damage but also play a significant role in the development of pulmonary fibrosis.

These signaling pathways could also be targeted to reduce microplastic-induced pulmonary fibrosis, opening new avenues for future treatments.

The angiotensin-converting enzyme-2 (ACE-2) alters the pathophysiology of various fatal cardiovascular diseases, including ischemic heart disease, whereas angiotensin 1-7 (Ang 1-7) exerts a wide range of actions. The effects of ischemia-reperfusion (IR) injury include damage to myocardial tissue that initiates protease action, causing cardiac cell death. Angiotensin- II (Ang-II) contributes through the renin-angiotensin system (RAS) to the IR injury, whereas Ang 1-7 paradoxically exerts a protective effect through the same. Thus, the myocardial ischemic reperfusion injury (MIRI) may be altered by the RAS of the heart. This review paper focuses on ACE-2, angiotensin-converting enzyme (ACE), and Ang 1-7 regulation in the RAS of the heart in the pathophysiology of MIRI. The treatment in such conditions using ACE-2 activator, ACE inhibitor, and Ang-II antagonists may promote vascular functions as well as cardio- protection.

The Na, K-ATPase generates an asymmetric ion gradient that supports multiple cellular functions, including the control of cellular volume, neuronal excitability, secondary ionic transport, and the movement of molecules like amino acids and glucose. The intracellular and extracellular levels of Na+ and K+ ions are the classical local regulators of the enzyme's activity. Additionally, the regulation of Na, K-ATPase is a complex process that occurs at multiple levels, encompassing its total cellular content, subcellular distribution, and intrinsic activity. In this context, the enzyme serves as a regulatory target for hormones, either through direct actions or via signaling cascades triggered by hormone receptors. Notably, FXYDs small transmembrane proteins regulators of Na, K-ATPase serve as intermediaries linking hormonal signaling to enzymatic regulation at various levels. Specifically, members of the FXYD family, particularly FXYD1 and FXYD2, are that undergo phosphorylation by kinases activated through hormone receptor signaling, which subsequently influences their modulation of Na, K-ATPase activity. This review describes the effects of FXYD2, cardiotonic steroid signaling, and hormones such as angiotensin II, dopamine, insulin, and catecholamines on the regulation of Na, K-ATPase. Furthermore, this review highlights the implications of Na, K-ATPase in diseases such as hypertension, renal hypomagnesemia, and cancer.

Over the last few years, COVID-19 has attracted medical attention both in terms of healthcare system reorganization and research. Among the different cardiovascular complications of the SARS-CoV-2 infection, cardiac arrhythmias represent an important clinical manifestation requiring proper therapy both in the acute and post-acute phase. The multiparametric in-hospital monitoring of COVID-19 patients frequently detects new-onset or recurrent cardiac arrhythmias. As many patients are monitored remotely from cardiology departments, this setting calls for proper arrhythmia interpretation and management, especially in critically ill patients in the intensive care unit. From this perspective, the possible pathophysiologic mechanisms and the main clinical manifestations of brady- and tachyarrhythmias in COVID-19 patients are briefly presented. The progressively increasing body of evidence on pathophysiology helps to identify the reversible causes of arrhythmias, better clarify the setting in which they occur, and establish their impact on prognosis, which are of paramount importance to orient decision making. Despite the accumulating knowledge on this disease, some dilemmas in the management of these patients may remain, such as the need to implant in the acute or post-acute phase a permanent pacemaker or cardioverter/defibrillation in patients presenting with brady- or tachyarrhythmias and lifelong oral anticoagulation in new-onset atrial fibrillation detected during SARS-CoV-2 infection.

Angiotensin II (ANG II) has been shown to have central nervous system effects. Although tissue renin-angiotensin systems (RAS) have been demonstrated in multiple tissues, the existence of a brain RAS is still a matter of debate. These studies test for angiotensin release from brain slices prepared from adult male Sprague-Dawley rats and male and female renin knock-out rats using Chinese hamster ovary cells modified to express both the angiotensin II type 1 receptor and a fluorescent calcium indicator. Sniffer cells were placed on the slices and calcium transients were measured from those located on or adjacent to the median preoptic nucleus with and without stimulation of the subfornical organ. Bath application of tetrodotoxin (1 µM) significantly attenuated spontaneous events while abolishing evoked sniffer cell activity. Bath application of dl-AP4 (10 µM, glutamatergic antagonist) did not affect either spontaneous or evoked release. Incubating the slices with fluorocitrate to inactive astrocytes did not influence sniffer cell activity in the MnPO. Pharmacological experiments indicate that ANG II release is largely both renin (aliskiren 10 µM) and ACE-1 (captopril 100 µM) dependent. However, experiments with brain slices prepared from male and female Renin knock-out rats suggest that alternative synthetic pathways may exist. Finally, these studies demonstrate that increases in ANG II release are observed following 7 days of chronic intermittent hypoxia. These studies suggest the existence of a tissue-specific RAS in the brain that involves canonical and alternative ANG II synthetic pathways and is upregulated in an animal model of sleep apnea.NEW & NOTEWORTHY These studies used Chinese hamster ovary cells that were cloned to express an angiotensin receptor (At1ra) and a calcium indicator (R-GECO) to detect the release of angiotensin from brain slices containing the lamina terminalis of rats. Some of the experiments use tissue from renin knockout rats. The results support the existence of an angiotensin system in the brain that may involve alternative synthetic pathways and is upregulated by intermittent hypoxia.

The renin-angiotensin-aldosterone system (RAAS) is a crucial regulator of the cardiovascular system and a target for widely used therapeutic drugs. Dysregulation of RAAS, implicated in prevalent diseases like hypertension and heart failure, has recently gained attention in oncological contexts due to its role in tumor biology and cardiovascular toxicities (CVTs). Thus, RAAS inhibitors (RAASi) may be used as potential supplementary therapies in cancer treatment and CVT prevention. Oncological treatments have evolved significantly, impacting patient survival and safety profiles. However, they pose cardiovascular risks, necessitating strategies for mitigating adverse effects. The main drug classes used in oncology include anthracyclines, anti-HER2 therapies, immune checkpoint inhibitors (ICIs), and vascular endothelial growth factor (VEGF) signaling pathway inhibitors (VSPI). While effective against cancer, these drugs induce varying CVTs. RAASi adjunctive therapy shows promise in enhancing clinical outcomes and protecting the cardiovascular system. Understanding RAAS involvement in cancer and CVT can inform personalized treatment approaches and improve patient care.

Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted.

Lactate is a commonly used biomarker for sepsis, although it has limitations in certain cases, suggesting the need for novel biomarkers. We evaluated the diagnostic accuracy of plasma renin concentration and renin activity for mortality and kidney outcomes in patients with sepsis with hypoperfusion or hypotension.

This was a multicenter, prospective, observational study of 117 patients with septic shock treated at three tertiary emergency departments between September 2021 and October 2022. The accuracy of renin activity, renin, and lactate concentrations in predicting 28-day mortality, acute kidney injury (AKI), and renal replacement requirement was assessed using the area under the ROC curve (AUC) analysis.

The AUCs of initial renin activity, renin, and lactate concentrations for predicting 28-day mortality were 0.66 (95% confidence interval [CI], 0.55-0.77), 0.63 (95% CI, 0.52-0.75), and 0.65 (95% CI, 0.53-0.77), respectively, and those at 24 hrs were 0.74 (95% CI, 0.62-0.86), 0.70 (95% CI, 0.56-0.83), and 0.67 (95% CI, 0.54-0.79). Renin concentrations and renin activity outperformed initial lactate concentrations in predicting AKI within 14 days. The AUCs of renin and lactate concentrations were 0.71 (95% CI, 0.61-0.80) and 0.57 (95% CI, 0.46-0.67), respectively (P=0.030). The AUC of renin activity (0.70; 95% CI, 0.60-0.80) was also higher than that of lactate concentration (P=0.044).

Renin concentration and renin activity show comparable performance to lactate concentration in predicting 28-day mortality in patients with septic shock but superior performance in predicting AKI.

Despite advances in surgical techniques and rehabilitation protocols, arthrofibrosis following total knee arthroplasty (TKA) still has poor outcomes. In the last decade, attention has been focused on the pathogenesis and cascade of events leading to the development of fibrosis. Currently, one of the most promising approaches consists in the indirect antagonisation of transforming growth factor beta 1 (TGF-beta 1) through the downregulation of the renin-angiotensin-aldosterone system (RAAS). This systematic review aims to analyse the available evidence regarding the use of angiotensin receptor blockers (ARBs)/angiotensin-converting-enzyme inhibitors (ACEi) in order to prevent post-operative knee arthrofibrosis following TKA.

Extensive research on the PubMed, Cochrane, and Google Scholar databases was performed on 8 July 2024, using keywords related to ARBs, ACE inhibitors and arthrofibrosis. Inclusion criteria included: (1) clinical trials of any level of evidence; (2) written in English; (3) studies conducted on humans; and (4) evaluating the antifibrotic effects of ACE inhibitors or ARBs administered for TKA surgeries. Exclusion criteria were articles written in other languages; preclinical studies; expert opinions; reviews and trials evaluating the effects of ACEi/ARBs not related to their antifibrotic effect after TKA.

A total of six studies met the inclusion criteria and were analysed. All studies were retrospective and involved a total of 158,310 patients. Time of administration varied among the studies as well as the dosage, which fell within the range for cardiological use. Four out of six studies focused exclusively on losartan. Three studies reported a clear, significant correlation between the use of ARBs and/or ACEi and a reduced likelihood of developing arthrofibrosis.

The RAAS antagonism could have potential for stiffness prevention after TKA. However, given the side effects and the limited evidence available, the use of ACEi/sartans for the sole purpose of avoiding arthrofibrosis after TKA is not currently recommended.

Level III.

Fibrosis after nephrotoxic injury is common. Activation of the paraventricular nucleus (PVN) renin-angiotensin system (RAS) and sympathetic nervous system (SNS) are common mechanism of renal fibrosis. However, there have limited knowledge about which brain regions are most affected by Angiotensin II (Ang II) after nephrotoxic injury, what role does Angiotensin II type 1a receptors (AT1R) signaling play and how this affects the outcomes of the kidneys.

In nephrotoxic folic acid-induced chronic kidney disease (FA-CKD) mouse models, we have integrated retrograde tracer techniques with studies on AT1afl/fl mice to pinpoint an excessively active central pathway that connects the paraventricular nucleus (PVN) to the rostral ventrolateral medulla (RVLM). This pathway plays a pivotal role in determining the kidney's fibrotic response following injury induced by folic acid.

FA-CKD (vs sham) had increased in the kidney SNS activity and Ang II expression in the central PVN. The activation of Ang II in the PVN triggers the activation of the PVN-RVLM pathway, amplifies SNS output, thus facilitating fibrosis development in FA-CKD mouse. Blocking sympathetic traffic or deleting AT1a in the PVN alleviated renal fibrosis in FA-CKD mice.

The FA-CKD mice have increased the expression of Ang II in PVN, thereby activating AT1a-positive PVN neurons project to the RVLM, where SNS activity is engaged to initiate fibrotic processes. The Ang II in PVN may contribute to the development of kidney fibrosis after nephrotoxic folic acid-induced kidney injury.

Angiotensin II is a recently introduced vasopressor, which has been available since 2017. The novelty and the relatively high cost of angiotensin II currently limit its broader application. It induces vasoconstriction by activating the renin-angiotensin-aldosterone system and is currently the sole vasopressor functioning through this pathway. Beyond vasoconstriction, angiotensin II also affects various other physiological processes. Current evidence supports its use in managing vasoplegic and cardiogenic shock in patients who are unresponsive to catecholamines and vasopressin. However, due to limited data, the optimal timing for initiating therapy with angiotensin II, strategies for combining it with other vasopressors, and strategies for its discontinuation remain unclear. Ongoing and planned studies aim to address some of these uncertainties. This article reviews the physiological and pathophysiological effects of angiotensin II, describes its pharmacology, and provides a narrative review of the current literature.

Inflammatory bowel disease is challenging to diagnose. Fecal biomarkers offer noninvasive solutions. The renin-angiotensin-aldosterone system is implicated in intestinal inflammation. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) regulate its activity, but conflicting findings on these enzymes in colitis require further investigation. We aimed to assess ACE and ACE2 presence and activities in the feces, serum, and colon of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rats.

Colitis was induced in male rats by rectal instillation of a 21% ethanolic TNBS solution. After rats' sacrifice, colonic portions, serum, and feces were collected. ACE and ACE2 presence in the feces was analyzed by western Blot, and colonic and serum enzymes' concentrations were quantified using ELISA kits. ACE activity was assessed using Hippuryl-His-Leu and Z-Phe-His-Leu as substrates. ACE2 activity was assessed using Mca-APK (Dnp) as a substrate in the presence and absence of DX600 (ACE2 inhibitor).

An ACE isoform of ~70 kDa was found only in the feces of TNBS-induced rats. ACE concentration was higher than that of ACE2 in the serum and the inflamed colon. ACE N-domain activity was higher than that of the C-domain in all matrices. ACE2 activity was higher in the feces of TNBS-induced animals compared to controls.

A 70 kDa ACE isoform only detected in the feces of TNBS-induced rats may have translational relevance. ACE N-domain seems to play a significant role in regulating colonic lesions. Further research using human samples is necessary to validate these findings.

We aimed to investigate the incidence, prenatal factors and outcomes of twin-to-twin transfusion (TTTS) with right ventricular outflow tract obstruction (RVOTO).

A systematic search was conducted to identify relevant studies published until February 2023 in English using the databases PubMed, Scopus and Web of Science. Studies reporting on pregnancies with TTTS and RVOTO were included. The random-effect model pooled the mean differences or odds ratios (OR) and the corresponding 95% confidence intervals. Heterogeneity was assessed using the I2 value.

A total of 17 studies encompassing 4332 TTTS pregnancies, of which 225 cases had RVOTO, were included. Incidence of RVOTO at time of TTTS diagnosis was 6%. In all, 134/197 (68%) had functional pulmonary stenosis and 62/197 (32%) had functional pulmonary atresia. Of these, 27% resolved following laser and 55% persisted after birth. Of those persisting, 27% required cardiac valve procedures. Prenatal associations were TTTS stage III (53% vs 39% in no-RVOTO), stage IV TTTS (28% in RVOTO vs 12% in no-RVOTO) and ductus venosus reversed a-wave (60% in RVOTO vs 19% in no-RVOTO). Gestational age at laser and gestational age at delivery were comparable between groups. Survival outcomes were also comparable between groups, including fetal demise of 26%, neonatal death of 12% and 6-month survival of 82% in RVOTO group. Findings were similar when subgroup analysis was done for studies including head-to-head analysis.

RVOT occurs in about 6% of the recipient twins with TTTS, especially in stages III and IV and those with reversed ductus venosus a-wave. The findings from this systematic review support the need for a thorough cardiac assessment of pregnancies complicated by TTTS, both before and after laser, to maximize perinatal outcome, and the importance of early diagnosis of TTTS and timely management.

Leukoaraiosis (LA) appears as white matter hyperintensities on T2-weighted brain magnetic resonance imaging scans. Age and hypertension are considered the primary risk factors for LA, but its pathogenesis remains uncertain. This study aims to investigate the correlation between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and LA. A total of 140 patients with LA and 136 neuroimaging alteration-free controls were recruited in a case-control study. ACE I/D polymorphism was determined using the polymerase chain reaction method. The allele and genotype distributions of the ACE I/D polymorphism were significantly different between subjects with and without LA. Significant difference was observed in the genotypic distribution between LA patients and controls for recessive and additive models. A statistically significant association remained apparent after adjusting for potential risk factors (D/D vs. I/D + I/I: adjusted OR 3.251, 95% CI 1.185-8.918; D/D vs. I/I: adjusted OR 3.277, 95% CI 1.187-9.047). Our results indicate that the D/D genotype and D allele are important risk factors for LA. Future studies with larger populations are needed to validate our results.

Apelin receptor (APJ), a member of the class A family of G protein-coupled receptor (GPCR), plays a crucial role in regulating cardiovascular and central nervous systems function. APJ influences the onset and progression of various diseases such as hypertension, atherosclerosis, and cerebral stroke, making it an important target for drug development. Our preliminary findings indicate that APJ can form homodimers, heterodimers, or even higher-order oligomers, which participate in different signaling pathways and have distinct functions compared with monomers. APJ homodimers can serve as neuroprotectors against, and provide new pharmaceutical targets for vascular dementia (VD). This review article aims to summarize the structural characteristics of APJ dimers and their roles in physiology and pathology, as well as explore their potential pharmacological applications.

Gastrodin, an anti-inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin-angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC-1 astrocytes treated with BV-2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre-treatment by RT-PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC-1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC-1 astrocytes responded vigorously to BV-2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF-1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS-SIRT3.

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.

The study explores the intricate relationship between aging and the development of noncommunicable diseases [NCDs], focusing on whether these diseases are inevitable consequences of aging or primarily driven by lifestyle factors. By examining epidemiological data, particularly from hunter-gatherer societies, the study highlights that many NCDs prevalent in modern populations are rare in these societies, suggesting a significant influence of lifestyle choices. It delves into the mechanisms through which poor diet, smoking, and other lifestyle factors contribute to systemic physiological imbalances, characterized by oxidative stress, insulin resistance and hyperinsulinemia, and dysregulation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the immune system. The interplay between this pattern and individual factors such as genetic susceptibility, biological variability, epigenetic changes and the microbiome is proposed to play a crucial role in the development of a range of age-related NCDs. Modified biomolecules such as oxysterols and advanced glycation end products also contribute to their development. Specific diseases such as benign prostatic hyperplasia, Parkinson's disease, glaucoma and osteoarthritis are analyzed to illustrate these mechanisms. The study concludes that while aging contributes to the risk of NCDs, lifestyle factors play a crucial role, offering potential avenues for prevention and intervention through healthier living practices. One possible approach could be to try to restore the physiological balance, e.g. through dietary measures [e.g. Mediterranean diet, Okinawan diet or Paleolithic diet] in conjunction with [a combination of] pharmacological interventions and other lifestyle changes.

Disturbance in neuroendocrine signaling has been consistently documented in multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS) representing the main cause of non-traumatic brain injury among young adults. In fact, MS patients display altered hormonal levels and psychiatric symptoms along with the pathologic hallmarks of the disease, which include demyelination, neuroinflammation and axonal injury. In addition, we have recently shown that extensive transcriptional changes take place in the hypothalamus of mice upon the MS model experimental autoimmune encephalomyelitis (EAE). We also detected structural and functional aberrancies in endocrine glands of EAE animals. Specifically, we described the hyperplasia of adrenal glands and the atrophy of ovaries at disease peak. To further expand the characterization of these phenotypes, here we profiled the transcriptomes of both glands by means of RNA-seq technology. Notably, we identified fatty acid and cholesterol biosynthetic pathways as the most dysregulated molecular processes in adrenals and ovaries, respectively. Furthermore, we demonstrated that key genes encoding neuropeptides and hormone receptors undergo distinct expression dynamics in the hypothalamus along disease progression. Altogether, our results corroborate the dysfunction of the neuroendocrine system as a major pathological event of autoimmune demyelination and highlight the crosstalk between the CNS and the periphery in mediating such disease phenotypes.

Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF.

In the first part of this article, the role of intestinal epithelial tight junctions (TJs), together with gastrointestinal dopaminergic and renin-angiotensin systems, are narratively reviewed to provide sufficient background. In the second part, the current experimental data on the interplay between gastrointestinal (GI) dopaminergic and renin-angiotensin systems in the regulation of intestinal epithelial permeability are reviewed in a systematic manner using the PRISMA methodology. Experimental data confirmed the copresence of DOPA decarboxylase (DDC) and angiotensin converting enzyme 2 (ACE2) in human and rodent enterocytes. The intestinal barrier structure and integrity can be altered by angiotensin (1-7) and dopamine (DA). Both renin-angiotensin and dopaminergic systems influence intestinal Na+/K+-ATPase activity, thus maintaining electrolyte and nutritional homeostasis. The colocalization of B0AT1 and ACE2 indicates the direct role of the renin-angiotensin system in amino acid absorption. Yet, more studies are needed to thoroughly define the structural and functional interaction between TJ-associated proteins and GI renin-angiotensin and dopaminergic systems.