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Many patients undergoing surgical procedures have a history of hypertension, diabetes mellitus, heart failure, or a combination. Often, these conditions involve the chronic use of a renin–angiotensin system inhibitor, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Observational studies have suggested that continuing ACEIs/ARBs before major noncardiac surgery can increase the risk of intraoperative hypotension, which might drive postoperative complications such as acute kidney injury, myocardial injury, or stroke. Strong recommendations on how to manage ACEIs/ARBs before surgery are, however, lacking owing to insufficient evidence, mostly limited to data from observational studies. Recently, the SPACE trial investigated the impact of preoperative management of ACEIs/ARBs on postoperative myocardial injury. Myocardial injury occurred in 48.3% patients randomised to discontinue and 41.3% patients randomised to continue ACEI/ARB (odds ratio for continuing: 0.77, 95% confidence interval 0.45–1.31). Patients randomised to the 'Stop' group experienced more postoperative hypertension. In a post hoc analysis, patients randomised to the 'Continue' group with low preoperative NT-proBNP concentrations (<100 pg ml−1) experienced less myocardial injury after surgery than the 'Stop' group, whereas no significant difference was observed in patients with elevated preoperative NT-proBNP concentrations. The SPACE trial provides important and new reassuring data on the safety of continuing ACEIs/ARBs before major surgery, challenging previous beliefs. [ABSTRACT FROM AUTHOR]

Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml−1) experience more complications after noncardiac surgery. Individuals prescribed renin–angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L−1 or a ≥5 ng L−1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L−1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml −1) and stopping or continuing RAS inhibitors. Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml −1 (median 339 [160–833] pg ml−1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml−1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml −1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05–5.99); P <0.0001}. For subjects with preoperative NT-proBNP <100 pg ml−1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06–4.65]; P =0.03). For preoperative NT-proBNP >100 pg ml−1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44–2.22]). Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml −1) increased the likelihood of myocardial injury before noncardiac surgery. [ABSTRACT FROM AUTHOR]

Currently, limited data exist regarding the pathological changes occurring during the incubation phase of SARS-CoV-2 infection. We utilized proteomic analysis to explore changes in the circulatory host response in individuals with SARS-CoV-2 infection before the onset of symptoms. Participants were individuals from a randomized clinical trial of prophylaxis for COVID-19 in a workers' dormitory. Proteomic signatures of blood samples collected within 7 days before symptom onset (incubation group) were compared with those collected >21 days (non-incubation group) to derive candidate biomarkers of incubation. Candidate biomarkers were assessed by comparing levels in the incubation group with both infected individuals (positive controls) and non-infected individuals (negative controls). The study included men (mean age 34.2 years and standard deviation 7.1) who were divided into three groups: an incubation group consisting of 44 men, and two control groups—positive (n = 56) and negative (n = 67) controls. Through proteomic analysis, we identified 49 proteins that, upon pathway analyses, indicated an upregulation of the renin-angiotensin and innate immune systems during the virus incubation period. Biomarker analyses revealed increased concentrations of plasma angiotensin II (mean 731 vs. 139 pg/mL), angiotensin (1–7) (302 vs. 9 pg/mL), CXCL10 (423 vs. 85 pg/mL), CXCL11 (82.7 vs. 32.1 pg/mL), interferon-gamma (0.49 vs. 0.20 pg/mL), legumain (914 vs. 743 pg/mL), galectin-9 (1443 vs. 836 pg/mL), and tumour necrosis factor (20.3 vs. 17.0 pg/mL) during virus incubation compared with non-infected controls (all p < 0.05). Plasma angiotensin (1–7) exhibited a significant increase before the onset of symptoms when compared with uninfected controls (area under the curve 0.99, sensitivity 0.97, and specificity 0.99). Angiotensin (1–7) could play a crucial role in the progression of symptomatic COVID-19 infection, and its assessment could help identify individuals who would benefit from enhanced monitoring and early antiviral intervention. [ABSTRACT FROM AUTHOR]

• A mechanism-based hybrid model, coupling target-mediated drug disposition and a minimal model of the renin-angiotensin system, was developed to characterize the pharmacokinetic and pharmacodynamic properties of enalaprilat, administered as the prodrug enalapril, in humans. • Model-based simulations of the final model predicted about a 6- to 7-fold shift in the enalaprilat ex vivo potency from its in vivo binding affinity, which is consistent with both observations and theoretical expectations of pharmacological antagonists that exhibit target-mediated drug disposition (TMDD). • Empirical functions based on operational models of agonism/antagonism were also derived that similarly suggest a role of drug, angiotensin, and total receptor concentration in the shift in enalaprilat ex vivo potency from in vivo binding affinity. Drug effects are often assumed to be directly proportional to the fraction of occupied targets. However, for a number of antagonists that exhibit target-mediated drug disposition (TMDD), such as angiotensin-converting enzyme (ACE) inhibitors, drug binding to the target at low concentrations may be significant enough to influence pharmacokinetics but insufficient to elicit a drug response (i.e., differences in drug-target binding affinity and potency). In this study, a pharmacokinetic/pharmacodynamic model for enalaprilat was developed in humans to provide a theoretical framework for assessing the relationship between ex vivo drug potency (IC 50) and in vivo target - binding affinity (K D). The model includes competitive binding of angiotensin I and enalaprilat to ACE and accounts for the circulating target pool. Data were obtained from the literature, and model fitting and parameter estimation were conducted using maximum likelihood in ADAPT5. The model adequately characterized time-courses of enalaprilat concentrations and four biomarkers in the renin-angiotensin system and provided estimates for in vivo K D (0.646 nM) and system-specific parameters, such as total target density (32.0 nM) and fraction of circulating target (19.8%), which were in agreement with previous reports. Model simulations were used to predict the concentration-effect curve of enalaprilat, revealing a 6.3-fold increase in IC 50 from K D. Additional simulations demonstrated that target reserve and degradation parameters are key factors determining the extent of shift of enalaprilat ex vivo potency from its in vivo binding affinity. This may be a common phenomenon for drugs exhibiting TMDD and has implications for translating binding affinity to potency in drug development. [ABSTRACT FROM AUTHOR]

• Hypertensive AF patients were on ACE-I in 36.9%, ARBs in 31.7% and D -CCB in 16.3%. • ACE-I, α-blockers and D -CCB were more common in men. • Women were more frequently on ARBs, thiazide diuretics and β-blockers. • ACE-I and ARBs were inversely associated with mortality risk in AF patients. Arterial hypertension is the most common cardiovascular comorbidity in atrial fibrillation (AF). Few studies investigated management strategies of hypertension in AF. We included 5769 AF patients on oral anticoagulants from the nationwide ongoing Italian START registry. We investigated the prescription of antihypertensive drugs and mortality risk. Subgroup analyses according to sex and major cardiovascular comorbidities were performed. Mean age was 80.8 years, 46.1% were women; 80.3% of patients were hypertensive. Furosemide (30.1%) was the most frequent diuretic followed by hydrochlorothiazide (15.4%) and potassium canrenoate (7.9%). 61.1% received β-blockers: 34.2% bisoprolol, 6.2% atenolol. Additionally, 36.9% were on angiotensin converting enzyme inhibitors (ACE-I): ramipril (20.9%), enalapril (5.3%) and perindopril (2.8%); 31.7% were on angiotensin receptors blockers (ARBs): valsartan (7.6%) and irbesartan (6.4%). Amlodipine and lercanidipine were prescribed in 14.0% and 2.3%, respectively. ACE-I (p < 0.001), α-blockers (p = 0.020) and Dihydropyridines calcium channel blockers (p = 0.004) were more common in men, while ARBs (p = 0.008), thiazide diuretics (p < 0.001) and β-blockers (p < 0.001) in women. During 22.61 ± 17.1 months, 512 patients died. Multivariable Cox regression analysis showed that ACE-I (Hazard ratio [HR] 0.758, 95% Confidence Interval [95%CI] 0.612–0.940, p = 0.012) and ARBs (HR 0.623, 95%CI 0.487–0.796, p < 0.001) inversely associated with mortality. ACE-I/ARBs inversely associated with mortality in both sexes and in patients with diabetes. This associastion was evident for ACE-I in patients with previous cardiovascular disease, and for ARBs in HF. A lower mortality risk was found in AF patients on ACE-I/ARBs. Different prescription patterns of antihypertensive drugs between men and women do exist. [Display omitted] [ABSTRACT FROM AUTHOR]

• The impact of hyperkalemia in the down-titration or reduction of HF therapy is well known. • Patiromer and sodium zirconium cyclosilicate are new treatment available for hyperkalemia. • Patiromer and sodium zirconium cyclosilicate were significantly associated with heart failure therapy optimization, reduction of hyperkalemia events and reduction of mean potassium levels, albeit with a higher rate of hypokalemia events. • Trials evaluating whether this heart failure therapy optimization results in a lower incidence of major adverse cardiovascular events are now needed. Hyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. PubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4–26%), decreased hyperkalemia events by 29% (95% CI: 55–92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18–0.44) compared to placebo, maintaining a good safety profile. NPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. CRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811 NPB in HF: A new therapeutic approach for an old problem Caption: CI, confidence interval; GI, gastrointestinal; HF, heart failure; NPB, novel potassium binders; RAASi, RAAS inhibitors; RCT, randomized controlled trial; RR, relative risk; SZC, sodium zirconium cyclosilicate. [Display omitted] [ABSTRACT FROM AUTHOR]

The development of mutant-selective KRAS inhibitors represents a major therapeutic advance; however, patients can develop resistance through feedback mechanisms and genetic alterations in the RAS pathway. Three publications in Nature and Cancer Discovery describe a promising RAS(ON) multi-selective inhibitor that simultaneously targets oncogenic RAS and multiple potential resistance mechanisms while sparing normal tissue. The development of mutant-selective KRAS inhibitors represents a major therapeutic advance; however, patients can develop resistance through feedback mechanisms and genetic alterations in the RAS pathway. Three publications in Nature and Cancer Discovery describe a promising RAS (on) multi-selective inhibitor that simultaneously targets oncogenic RAS and multiple potential resistance mechanisms while sparing normal tissue. [ABSTRACT FROM AUTHOR]

• Albuminuria is a feature that by itself defines kidney disease and is associated with an increased risk of cardiovascular disease, systemic inflammation and malignancy. • Albuminuria may cause inflammation and loss of key tubular functions such as production of Klotho or calcitriol that may contribute to malignancy. • Albuminuria lowering treatment strategies may decrease inflammation and the risk for development of malignancy. Cancer is the second leading cause of death among the adult population following cardiovascular diseases. Prevention and earlier diagnosis are among the cornerstones in the management of malignancies. Albuminuria is a diagnostic criterion for chronic kidney disease and has been associated with multiple conditions including cardiovascular diseases and systemic inflammation while the association between albuminuria and malignancy has been inadequately addressed. Large-scale observational studies with long follow-up periods demonstrate a statistically significant association between albuminuria and overall malignancy incidence, especially urothelial malignancy incidence. However, the underlying pathophysiology linking these two entities is not a straightforward causal relationship but most likely a multidirectional relationship including a causal link. In this narrative review, we evaluate the clinical studies investigating the association between albuminuria and malignancy along with potential underlying mechanisms linking them. We also summarize data on the impact of treatment modalities prescribed for albuminuria and/or proteinuria on the prevention or prognosis of malignancies. • Albuminuria has been associated with a higher risk of overall malignancies. However, the molecular mechanisms involved, and the clinical practice consequences are poorly understood. • Recent guidance from Scientific Societies has expanded the target population for albuminuria screening program. • Additionally, recent clinical trials have expanded the range of drugs that lower albuminuria for renin-angiotensin system blockers to also include mineralocorticoid receptor antagonists, SGLT2 inhibitors and GLP-1 receptor agonists. This has resulted in changes in the clinical guidelines on the treatment of albuminuria in diabetic and non-diabetic individuals. • Implementation of recent clinical guidance documents on the screening and treatment of albuminuria will provide a unique opportunity to more thoroughly assess the association of albuminuria with the risk of malignancy and explore the impact of albuminuria-lowering drugs on this risk. • The design and implementation of prospective studies, ideally pragmatic clinical trials are the optimal way to assess the association of albuminuria with malignancy and the impact of albuminuria-lowering drugs. • Absent this, the post-hoc analyses of prospectively collected information from healthcare and mortality databases will offer additional research opportunities. • This information may be eventually used to develop clinical guidance documents on the screening and treatment of albuminuria in individuals at high risk of malignancy. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP)/Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. miRNAs are 21 to 23 nucleotides of small RNAs that posttranscriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p/miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p/miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression. [ABSTRACT FROM AUTHOR]

The role of the renin-angiotensin-aldosterone axis in vasoplegia after cardiac surgery remains unclear. We tested the hypothesis that, compared with norepinephrine, infusion of angiotensin II titrated to achieve similar mean arterial pressure (MAP) would suppress plasma renin concentration (PRC) while maintaining aldosterone levels. In a double-blind, randomised controlled trial, subjects received either an infusion of angiotensin II or norepinephrine to maintain MAP 70–80 mm Hg from induction of anaesthesia. We compared PRC, aldosterone, dipeptidyl peptidase-3, and angiotensin-converting enzyme 2 activity between treatment groups, before surgery, on ICU admission, and 24 h after surgery. In 60 patients (11.7% female; mean age 68 yr [11 yr]), norepinephrine increased median PRC at ICU admission (median difference [MD] 46 [inter-quartile range, IQR, 3–88] μU ml−1; P <0.001) but angiotensin II did not (MD −3 [IQR −62 to 35] μU ml−1; P =0.36). Aldosterone levels increased with both. The aldosterone:PRC ratio did not change with norepinephrine (MD −0.01 [IQR −0.14 to 0.03] μU ml−1 per ng dl−1, P =0.76) but increased with angiotensin II (MD 0.05 [IQR 0.004–0.26] μU ml−1 per ng dl−1, P <0.001). The upper quartile of PRC before surgery was associated with higher vasopressor requirements when norepinephrine was used to maintain MAP, but not angiotensin II. Dipeptidyl peptidase-3 levels and angiotensin-converting enzyme 2 activities were similar at all time points. Angiotensin II suppressed renin release while maintaining aldosterone levels compared with norepinephrine. Higher plasma renin concentration before surgery was associated with greater vasopressor requirement for norepinephrine, but not angiotensin II. Australian and New Zealand Clinical Trials Registry—ACTRN12621000195853 23/02/2021. [ABSTRACT FROM AUTHOR]

• Guidelines recommend routine creatinine and potassium measurements for renal adverse event detection in whom Renin-Angiotensin-Aldosterone-System inhibitors (RAASi) are initiated. • Machine learning algorithms were used to evaluate RAASi-associated renal adverse events and their associated factors. • Index potassium and glucose levels were the most important factors associated with renal adverse events, and thiazide use reduced RAASi-associated hyperkalemia. • K-nearest neighbors, random forest, extreme gradient boosting, and neural network algorithms have the highest and similar performance metrics for renal adverse event prediction. Renin-angiotensin-aldosterone system inhibitors (RAASi) are commonly used medications. Renal adverse events associated with RAASi are hyperkalemia and acute kidney injury. We aimed to evaluate the performance of machine learning (ML) algorithms in order to define event associated features and predict RAASi associated renal adverse events. Data of patients recruited from five internal medicine and cardiology outpatient clinics were evaluated retrospectively. Clinical, laboratory, and medication data were acquired via electronic medical records. Dataset balancing and feature selection for machine learning algorithms were performed. Random forest (RF), k-nearest neighbor (kNN), naïve Bayes (NB), extreme gradient boosting (xGB), support vector machine (SVM), neural network (NN), and logistic regression (LR) were used to create a prediction model. 409 patients were included, and 50 renal adverse events occurred. The most important features predicting the renal adverse events were the index K and glucose levels, as well as having uncontrolled diabetes mellitus. Thiazides reduced RAASi associated hyperkalemia. kNN, RF, xGB and NN algorithms have the highest and similar AUC (≥ 98%), recall (≥ 94%), specifity (≥ 97%), precision (≥ 92%), accuracy (≥ 96%) and F1 statistics (≥ 94%) performance metrics for prediction. RAASi associated renal adverse events can be predicted prior to medication initiation by machine learning algorithms. Further prospective studies with large patient numbers are needed to create scoring systems as well as for their validation. [ABSTRACT FROM AUTHOR]

• The first comprehensive evaluation of efficacy and safety profile for therapeutic regimens despite optimized RAS blockade among IgA nephropathy patients at high risk of disease progression. • Dapagliflozin appeared to have the best comparative performance in end stage renal disease prevention and the lowest risk of serious adverse events. • Immunosuppressant was with the best comparative efficacy in promoting clinical remission and decreasing proteinuria, but with less robust safety profile. Approximately 20–40% of IgA nephropathy patients would develop end-stage renal disease, for whom safety concerns remained a major setback when using conventional pharmaceutical treatments. Evidence is lacking for optimal selection of effective and safe pharmaceuticals to slow the disease progression. To compare the effectiveness and safety profile of different treatments despite optimized RAS blockade for IgA nephropathy patients at high-risk of disease progression. PubMed, ScienceDirect and Web of science databases published from 1990 to March 18th, 2023 without language restriction. Immunosuppressant and cortico-steroid treatments were considered as two independent regimens. Fifteen trials with 1,983 participants were evaluated for the occurrence of five outcomes. For ESRD, dapagliflozin was superior to placebo (RR: 0.30; 95% CI 0.11, 0.80), immunosuppressant (RR:0.14; 95% CI 0.02,0.81) and RAS (RR:0.10; 95% CI 0.01,0.69). Glucocorticoid was superior to placebo (RR: 0.71; 95%CI 0.52,0.99). For clinical remission, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.87; 95%CI 1.60, 5.17). For 50% reduction in 24 h proteinuria or UPCR, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.40; 95%CI 1.04, 5.55). For SAE, dapagliflozin was superior to glucocorticoid (RR: 0.22; 95%CI 0.09, 0.54), whereas glucocorticoid was inferior to placebo (RR: 2.91; 95%CI 1.39, 6.07). Cluster ranking showed dapagliflozin appeared to have the lowest SAE risk and the best comparative therapeutic efficacy in preventing ESRD. The current findings highlighted dapagliflozin was a promising pharmaceutical treatment alternative to achieve optimal outcomes for IgA nephropathy patients at high risk of disease progression. PROSPERO CRD42022374418. [ABSTRACT FROM AUTHOR]

Renin–angiotensin–aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. We carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. In total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3–not reached) versus 15.2 (interquartile range 5.1–58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9–34.5) versus 5.0 (interquartile range 2.2–15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44–0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50–0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. The use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy. • RAASi were associated with improved clinical outcomes across a broad range of cancer patients receiving ICI. • Subgroup analysis showed that ARB were associated with improved clinical outcomes in patients undergoing immunotherapy. • The use of RAASi before immune checkpoint blockade was not associated with improved survival. • RAASi were not associated with increased risk of adverse events among cancer patients receiving ICI. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects. [Display omitted] ● Both cytokines and cytokine signaling pathways can be new therapeutic targets for IBD. ● The importance of conventional therapy for IBD, such as anti-TNF-α antibodies, cannot be ignored. ● Conventional and novel therapy options for IBD can complement each other. ● Novel small molecule drugs such as JAK inhibitor play an important role in the treatment of IBD. ● Novel biologics such as IL-12/23 inhibitors and integrin inhibitors reflect the advantages and development potential of precision medicine. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is an important fluid regulation system in the body, and excessive activation of the circulatory or local RAS can increase blood pressure (BP). Excess fluoride can increase BP, although the underlying mechanism related to activation of the RAS remains unclear. Thus, the aim of this study was to elucidate the role of the RAS in fluoride-induced hypertension. Markers of the circulating and local RASs related to pathological changes to the kidneys, myocardium, and aorta were measured. Fluoride reduced serum levels of renin, angiotensin II (Ang II), and angiotensin (1−7) [Ang (1−7)], and dysregulated plasma levels of aldosterone and potassium levels. Excess fluoride can damage the kidneys, myocardium, and aorta, overactivate the renal angiotensin converting enzyme (ACE)-Ang II-angiotensin type 1 receptor axis, and inhibit activation of the ACE2-Ang (1−7)-Mas axis, leading to dysregulation of alpha epithelial sodium channels and significantly increased expression of Ang II in the myocardium and aorta. Hence, excess fluoride can cause low-renin hypertension via an imbalance between the circulatory and local RASs. • Excess fluoride can lead to low-renin hypertension (LRH). • Fluoride influences aldosterone secretion. • Excess fluoride can inhibit the circulating renin-angiotensin system (RAS). • Excess fluoride can activate the renal and cardiovascular RASs. • The mechanism of LRH involves an imbalance between the circulatory and local RASs. [ABSTRACT FROM AUTHOR]

Diabetes is present in approximately 10% of people living with schizophrenia and substantially contributes to early mortality, but some aspects of diabetes care among those with schizophrenia have been inadequately investigated to date. We assessed diabetes care and comorbidity management among people with and without schizophrenia. We conducted a cohort study with data obtained from primary care electronic medical records stored in the Diabetes Action Canada (DAC) National Repository from Alberta, Ontario, and Quebec, Canada. The population studied included patients with diabetes, with and without schizophrenia, who had at least 3 primary care visits in a 2 year period between July 2017 and June 2019. Outcomes included glycemia; diabetes complication screening and monitoring; antihyperglycemic and cardioprotective medication prescription; health service use. We identified 69,512 patients with diabetes; 911 (1.3%) of whom also had schizophrenia. Prevalence of high HbA1C (>8.5%) (9083/68601; 13.2% vs. 137/911; 15.0%) and high blood pressure (>130/80 mmHg) (4248/68601; 6.2% vs. 73/911; 8.0%) was similar between the two groups. Half (50.0%) of patients with schizophrenia (n = 455) had 11 or more primary care visits in the past year, compared with 27.8% of people without schizophrenia. (p < 0.0001). Patients with schizophrenia had lower odds of ever having blood pressure recorded (OR = 0.81, 95% CI 0.71–0.94) and fewer of those with chronic kidney disease (CKD) were prescribed renin-angiotensin aldosterone system inhibitors, compared to patients without schizophrenia (10.3% vs 15.8%, p = 0.0005). Patients with diabetes and schizophrenia achieved similar blood glucose and blood pressure levels to those without schizophrenia, and had more primary care visits. However, they had fewer blood pressure readings and lower prescription of recommended medications among those who also had CKD. These results are both encouraging and represent opportunities for improvement in care. [ABSTRACT FROM AUTHOR]

Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension. The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort. Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively. Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65). Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes. [Display omitted] [ABSTRACT FROM AUTHOR]

Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury. C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy × 3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells. SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P =.0428) and negatively correlated with number of voids (P =.028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed. [ABSTRACT FROM AUTHOR]

• SARS-CoV-2 infection promotes the failure of the counter-regulatory RAS axis. • The failure of RAS is mediated by the binding of the spike protein of the virus with ACE2 (causing malfunction of these receptors). • The consequent accumulation of Ang II can directly contribute to development of high BP in the acute phase of infection. • Accrued data suggest that acute rise in BP is an independent predictor of bad outcome in COVID-19 patients. • A similar mechanism has been postulated to explain the rise in BP following COVID-19 vaccination ("Spike Effect"). Among the various comorbidities potentially worsening the clinical outcome in patients hospitalized for the acute respiratory syndrome coronavirus-2 (SARS-CoV-2), hypertension is one of the most prevalent. However, the basic mechanisms underlying the development of severe forms of coronavirus disease 2019 (COVID-19) among hypertensive patients remain undefined and the direct association of hypertension with outcome in COVID-19 is still a field of debate. Experimental and clinical data suggest that SARS-CoV-2 infection promotes a rise in blood pressure (BP) during the acute phase of infection. Acute increase in BP and high in-hospital BP variability may be tied with acute organ damage and a worse outcome in patients hospitalized for COVID-19. In this context, the failure of the counter-regulatory renin-angiotensin-system (RAS) axis is a potentially relevant mechanism involved in the raise in BP. It is well recognized that the efficient binding of the Spike (S) protein to angiotensin converting enzyme 2 (ACE2) receptors mediates the virus entry into cells. Internalization of ACE2, downregulation and malfunction predominantly due to viral occupation, dysregulates the protective RAS axis with increased generation and activity of angiotensin (Ang) II and reduced formation of Ang 1,7. Thus, the imbalance between Ang II and Ang 1–7 can directly contribute to excessively rise BP in the acute phase of SARS-CoV-2 infection. A similar mechanism has been postulated to explain the raise in BP following COVID-19 vaccination ("Spike Effect" similar to that observed during the infection of SARS-CoV-2). S proteins produced upon vaccination have the native-like mimicry of SARS-CoV-2 S protein's receptor binding functionality and prefusion structure and free-floating S proteins released by the destroyed cells previously targeted by vaccines may interact with ACE2 of other cells, thereby promoting ACE2 internalization and degradation, and loss of ACE2 activities. [Display omitted] [ABSTRACT FROM AUTHOR]

Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. 742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival. In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is a crucial risk factor for hypertensive disorders during pregnancy, but its progression during pregnancy remains unclear. We previously showed cardiac hypertrophy in a pregnancy-associated hypertensive (PAH) mouse model, in which an increase in angiotensin II (Ang II) levels was induced by human renin and human angiotensinogen, depending on pregnancy conditions. Here, to elucidate the factors involved in the progression of cardiac hypertrophy, we performed a comprehensive analysis of changes in gene expression in the hearts of PAH mice and compared them with those in control mice. We found that alpha-1A adrenergic receptor (Adra1a) mRNA levels in the heart were significantly reduced under PAH conditions, whereas the renin-angiotensin system was upregulated. Furthermore, we found that Adra1a-deficient PAH mice exhibited more severe cardiac hypertrophy than PAH mice. Our study suggests that Adra1a levels are regulated by renin-angiotensin system and that changes in Adra1a expression are involved in progressive cardiac hypertrophy in PAH mice. [ABSTRACT FROM AUTHOR]

Few interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients. This observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not. Patients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11–0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027). RASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients. • Serum chloride level affects renin-angiotensin-aldosterone system (RAS) in HFpEF patients. • Patients with low chloride level receiving RAS inhibitor had lower mortality rates. • Prognostic benefit of RAS inhibitor in HFpEF patients depended on baseline serum chloride levels. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the safety and effectiveness of sacubitril/valsartan (sac/val) for elderly patients with hypertension and heart failure in the real-world setting. Patients with established hypertension complicated with structural or functional impairment of ventricular fillings [New York Heart Association (NYHA) functional class II–IV)] were enrolled. The effectiveness of sac/val in terms of BP reduction and improvement in frailty and echocardiographic evaluation of cardiac function were examined from baseline to 6-month administration. Overall, 241 patients were treated with sac/val and 227 with renin angiotensin aldosterone system inhibitor (RAASi) for hypertension control. There were significant difference in the degree of systolic blood pressure reduction between two groups. Echocardiography showed that sac/val significantly improved left ventricular ejection fraction [4.0% (95% CI: 2.0–7.5) vs −1.0 (95% CI: −4.0–2.0), P = 0.001] during the follow-up visits. Significant improvements in NYHA function class and FRAIL scores post sac/val were observed after 3 and 6 month treatment. The rate of primary cardiovascular composite outcome was higher in patients in the RAASi group (26.9%; 95% CI: 19.6–34.0) than in the sac/val group (22.0%; 95% CI: 16.7–27.3). Sac/val may be useful not only for reducing BP, but also for improving the structural and functional parameters of echocardiography, eventually resulting in a significant improvement of the overall symptomatic status, a significant reduction in NYHA class, and functional improvement. • Sac/val could significantly reduced BP and serum NT-proBNP levels, as well as contribute to higher EF and lower LV mass by its impact on cardiovascular hemodynamics. • Participants receiving sac/val exhibited a significant improvement of overall symptomatic status with a significant reduction in NYHA-class and functional improvement evaluated by questionnaire-based measures of patientlevel activity in real-world settings. • Sac/val reduced the risks of composite cardiovascular events occurrence and of hospitalization of heart failure, as compared with RAASi. • The safety profile of sac/val was favorable in the balance of serum potassium. [ABSTRACT FROM AUTHOR]

The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin–angiotensin–aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation. Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients. We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9–7.5] years. Data on K+ levels were available in 7087 cases. Patients with K+ plasma level ≥ 5.6 mEq/L and < 4 mEq/L were excluded. Remaining patients were categorized into normal >4 and < 5 mEq/L (n = 4826, 68%) and moderately high ≥5.0 and ≤ 5.5 mEq/L (n = 496, 7%) K+. Then patients were matched by propensity score in 484 couplets of patients. MECKI score value was 7% [IQR 3.1–14.1%] and 7.3% [IQR 3.4–15%] (p = 0.678) in patients with normal and moderately high K+ values while cardiovascular mortality events at two years follow-up were 41 (4.2%) and 33 (3.4%) (p = 0.333) in each group respectively. Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients. • Hyperkalemia affects up to 18% of HFrEF patients leading to therapy down-titration. • The prognostic role of moderate hyperkalemia is still controversial. • We discovered that moderate hyperkalemia in HF is not associated to worst outcome. [ABSTRACT FROM AUTHOR]

• South African medicinal plants and bioactive compounds demonstrate antihypertensive potential via inhibitory effects on ACE in the RAAS pathway. • D. rotundifolia , 3β-taraxerol, β-amyrin, oleanolic acid, and quercetin exhibited strong nitric oxide inhibition. • D. rotundifolia, R. chirendensis and S. birrea demonstrates strong ACE inhibitory activity. Plants used in African traditional medicine to manage hypertension are potential angiotensin-converting enzyme (ACE) inhibitors. We, therefore, aimed to determine the antioxidant and anti-hypertensive properties of the methanol extracts of six plants, namely, Artemisia afra Jacq. ex Willd., Clausena anisata, Dombeya rotundifolia, Sclerocarya birrea, Rhus chirindensis, and Warbugia salutaris and selected compounds, viz., 3β-taraxerol, β-amyrin, oleanolic acid, hesperidin, nicotinamide, and quercetin. The antioxidant and anti-hypertensive activities were determined using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, the nitric oxide (NO) scavenging assay and the ACE inhibition assay respectively. D. rotundifolia (IC 50 : 63.02 ± 0.5 µg/mL), 3β-taraxerol (IC 50 : <1 µg/mL), β-amyrin (IC 50 : 105.04 ± 1.36 µg/mL), oleanolic acid (IC 50 : 32.20 ± 0.20 µg/mL) and quercetin (IC 50 : <1 µg/mL) displayed strong DPPH free radical scavenging activity ranging from 80 to 90%. Additionally, D. rotundifolia demonstrated 72% inhibition against NO displaying the lowest IC 50 of 63.45 ± 2.9 µg.mL. A 75–87% inhibition was noted for 3β-taraxerol (IC 50 : <1 µg/mL), β-amyrin (IC 50 : <1 µg/mL), oleanolic acid (IC 50 : <1 µg/mL) and quercetin (IC 50 : 125.02 ± 1.77 µg/mL), similar to ascorbic acid (standard). A significant ACE inhibitory activity of 92% with the lowest IC 50 (110.16 ± 0.12 µg.mL) was demonstrated for D. rotundifolia followed by R. chirendensis (79%), S. birrea (67%), A. afra (54%) and C. anisata (54%). Our findings suggest that these medicinal plants and bioactive compounds have great antihypertensive potential via inhibitory effects on ACE in the renin-angiotensin-aldosterone system pathway. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system inhibitor (RASi) and β-blocker provide prognostic benefits as guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). However, there is limited data for the favorable effects in such patients receiving regular hemodialysis. We aimed to evaluate the prognostic impact of RASi and β-blocker in patients with HFrEF who receive regular hemodialysis. In this retrospective, single-center, observational study, from 2110 consecutive patients hospitalized for HF and who survived to discharge, 97 with HFrEF who received regular hemodialysis were included for analysis. They were classified into three groups according to prescribed medication at discharge following index hospitalization: both RASi and β-blocker (Dual-GDMT group: n = 55), either RASi or β-blocker (Mono-GDMT group: n = 34), and neither RASi nor β-blocker (No-GDMT group: n = 8). The primary endpoint was a composite of all-cause death and rehospitalization for heart failure. The mean age was 66 years and 79% of the patients were men. During the median follow-up of 501 days, the primary endpoint occurred in 43 patients (44%). Kaplan-Meier analysis revealed that the Dual-GDMT group had the lowest rates of the primary endpoint (log-rank test for trend: p < 0.001). Even after adjustment for diverse covariates (multivariate Cox regression), the Dual-GDMT (hazard ratio [HR]: 0.04, 95% confidence interval (CI): 0.005–0.32) and Mono-GDMT (HR: 0.08, 95% CI: 0.01–0.50) groups had better prognoses than the No-GDMT group. The prescription of RASi and/or β-blocker was associated with a lower adverse-event rate after discharge in patients with HFrEF who were on regular hemodialysis. • Patients on regular hemodialysis were generally excluded from randomized outcome studies of heart failure. • Prognostic effect of guideline-directed medical therapy in patients with heart failure on regular hemodialysis is unknown. • RAS inhibitor and/or β-blocker therapy was associated with better clinical outcomes of HFrEF patients on hemodialysis. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) presenting with low blood pressure (BP) have been underrepresented in large-scale clinical trials. We investigated the characteristics and implementation of conventional guideline-directed medical therapy (GDMT; renin-angiotensin system inhibitors and β-blockers) in patients with low BP hospitalized for HF with systolic dysfunction. Conventional GDMT was evaluated by discharge BP among 2043 consecutive patients with HF and left ventricular ejection fraction (LVEF) < 50% in the WET-HF registry. Among the 708 (34.7%) patients with lower discharge BP (≤ 100 mmHg; the lower tertiles), exploratory subgroups included patients with previous HF hospitalization, inotrope use, New York Heart Association (NYHA) III–IV class, and lower estimated glomerular filtration rate (eGFR) and LVEF (lower than median value). We evaluated the risk-adjusted association between GDMT implementation and 2-year adverse events (all-cause mortality or HF rehospitalization). Among the 2043 patients (age 74 [63–82] years), the median systolic BP was 108 (98–120) mmHg. Among patients with lower BP, GDMT prescription rate was 62.7%, and GDMT use was associated with decreased adverse events (HR:0.74, 95%CI:0.58–0.94). GDMT prescription rates were lower among higher-NYHA class and lower-eGFR subgroups compared with their reference subgroups, and directionally similar outcomes were noted in all subgroups (favoring GDMT use); however, this association was somewhat attenuated in the lower-eGFR group (HR:0.87, 95%CI:0.64–1.17). Conventional GDMT use was associated with decreased adverse outcomes in most patients with HF compounded by systolic dysfunction and low BP, albeit caution is warranted in patients with renal dysfunction. • ≈60% of HF patients with systolic dysfunction and low BP received conventional GDMT. • Low BP was associated with worse long-term clinical outcomes. • Conventional GDMT use was associated with better clinical outcomes in low BP group. • The favorable prognostic effect of GDMT was consistent across all high-risk subgroups. • This association was somewhat attenuated in the lower-eGFR subgroup. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential clinical effects of renin-angiotensin system blocker (RASB, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database.Methods: One hundred and seven untreated, newly diagnosed PD patients with hypertension, from the PPMI were included. We measured cognitive performance, biomarkers in CSF, and magnetic resonance imaging (MRI) during the five follow-up years for patients exposed or not to renal-angiotensin system blockers. Sixteen PD patients with hypertension underwent [18F]florbetaben positron emission tomography (PET) scanning. SUVRs of region of interest (ROI) were calculated and compared within different groups.Result: Treatment with ARBs but not ACEIs improved global cognitive function evaluated by MoCA score in PD patients with hypertension compared to other hypertensive medicines up to 5 years follow up. Specifically, ARBs improved visuospatial, memory, executive abilities, processing speed attention test scores in PD. There was no significant impact of ARBs on α-syn, tau, Aβ in CSF. RASBs reduced [18F] florbetaben uptake in cortex and subcortex nuclei in the brain.Conclusions: These results show potential protective effect with ARBs in cognitive impairment of parkinson's disease with hypertension. [ABSTRACT FROM AUTHOR]

Mutations in one of the three RAS genes (HRAS, KRAS, and NRAS) are present in nearly 20% of all human cancers. These mutations shift RAS to the GTP-loaded active state due to impairment in the intrinsic GTPase activity and disruption of GAP-mediated GTP hydrolysis, resulting in constitutive activation of effectors such as RAF. Because activation of RAF involves dimerization, RAS dimerization has been proposed as an important step in RAS-mediated activation of effectors. The α4-α5 allosteric lobe of RAS has been proposed as a RAS dimerization interface. Indeed, the NS1 monobody, which binds the α4-α5 region within the RAS G domain, inhibits RAS-dependent signaling and transformation as well as RAS nanoclustering at the plasma membrane. Although these results are consistent with a model in which the G domain dimerizes through the α4-α5 region, the isolated G domain of RAS lacks intrinsic dimerization capacity. Furthermore, prior studies analyzing α4-α5 point mutations have reported mixed effects on RAS function. Here, we evaluated the activity of a panel of single amino acid substitutions in the α4-α5 region implicated in RAS dimerization. We found that these proposed "dimerization-disrupting" mutations do not significantly impair self-association, signaling, or transformation of oncogenic RAS. These results are consistent with a model in which activated RAS protomers cluster in close proximity to promote the dimerization of their associated effector proteins (e.g., RAF) without physically associating into dimers mediated by specific molecular interactions. Our findings suggest the need for a nonconventional approach to developing therapeutics targeting the α4-α5 region. [ABSTRACT FROM AUTHOR]

In 2013, the French National Health Insurance set up a programme to help patients with heart failure to return home and stay there (PRADO). During a hospitalization for cardiac decompensation, the medical team decides on the inclusion of the patient in the programme based on eligibility criteria defined. The objective of this study was to identify the factors most associated with the inclusion of heart failure patients in the PRADO program. This was a monocentric retrospective analytical stratified case-control study. It focused on the analysis of patient records hospitalized for cardiac decompensation between 01/01/2017 and 31/12/2018 in the cardiology department of the Centre Hospitalier de Troyes. For each patient included in the PRADO Heart Failure programme, one or two controls, not included in the PRADO Heart Failure programme were matched. The matching was exact without discounting. It was performed on the following criteria: age in 10-year increments, sex, main diagnosis of the stay, major category of diagnosis of the stay and its type (medical or surgical), the severity score of the Homogeneous Group of Patients of the stay and the Charlson score. A total of 40 patients included in PRADO Heart Failure were matched to 56 controls not included in PRADO Heart Failure. Patients with respiratory disease (3.77 [1.07 – 13.29]), as well as patients on renin-angiotensin system inhibitors (2.24 [1.61 – 5.31]) were more often included in the PRADO Heart Failure programme. The most frequent criteria for non-eligibility were the need to transfer the patient to a specialised institution and significant impairment of higher functions. Respiratory comorbidity and renin-angiotensin system blocker treatment are the factors most associated with the inclusion of heart failure patients in the PRADO Heart Failure programme. [ABSTRACT FROM AUTHOR]

Activation of the renin-angiotensin-aldosterone axis with elevation of inflammatory markers and the resulting fibrosis play a very important role in atrial remodeling in patients with atrial fibrillation (AF), which is associated with post-cardioversion recurrence. The purpose of the study was to describe the time course of angiotensin II (AngII), aldosterone, and of the amino terminal pro-peptide of type III pro-collagen (PIIINP) following cardioversion, and their association with arrhythmia recurrence. Ninety-nine subjects with long-standing, persistent, non-valvular atrial fibrillation who underwent successful electrical cardioversion were included, with a 6 month follow up. Angiotensin II (AngII), aldosterone and PIIINP concentrations were measured at 0, 1, 7, 30, and 180 d. Two groups were formed for the analysis: continuing sinus rhythm and recurrence of AF. 53% of the subjects experienced recurrence of AF. Subjects with recurrence had larger left atrial diameters and lower global peak atrial longitudinal strain (8.7 vs. 19.7%; p <0.001), higher levels of AngII (431.85 vs. 257.97 pg/mL; p = 0.003) at 180 d, higher pre-cardioversion levels of aldosterone, (11.42 vs. 5.46 pg/mL; p = 0.048) at 1 d (12.01 vs. 5.05 pg/mL; p = 0.004) and at 180 d (12.66 vs. 7.51 pg/mL; p = 0.011). There were no differences in PIIINP levels between both groups. Conclusions. Electrical post-cardioversion recurrence in subjects with long-standing, persistent AF is associated with elevated levels of AngII and aldosterone. [ABSTRACT FROM AUTHOR]

• Cancer incidence and cancer-related mortality of patients with heart failure are higher than those expected for the general population. • Increased sympathetic activity, renin-angiotensin-aldosterone system activation, chronic inflammation and oxidative stress are proposed biological mechanisms to explain the increased risk of cancer in patients with heart failure. • Prognosis of patients with heart failure and co-existing malignancies is poor, with mortality rates that exceed 40% during the first year after cancer diagnosis. To assess the incidence of cancer diagnosis and cancer-related mortality in patients with heart failure (HF). Observational study based in a prospective cohort of patients with HF referred to a specialized Spanish clinic between 2010 and 2019. The observed incidence of malignancies (excluding non-melanoma skin cancer) was compared to that expected for the general Spanish population according to the Global Cancer Observatory. We studied 1909 consecutive patients with HF. Over a median follow-up of 4.07 years, 165 new cases of malignancy were diagnosed. Observed age-standardized incidence rates of cancer were 861 (95% CI 618.4–2159.4) cases per 100,000 patients-years in men and 728.5 (95% CI 451.1–4308.7) cases per 100,000 patients-years in women; while age-standardized incidence rates of cancer expected for the general Spanish population were 479.4 cases per 100,000 patients-years in men (risk ratio = 1.80) and 295.5 cases per 100,000 patients-years in women (risk ratio = 2.46). Both a history of pre-existing malignancy at baseline and the development of new malignancies during follow-up were associated with reduced survival. Observed age-standardized cancer-related mortality was 344.1 (95% CI 202.1–1675) deaths per 100,000 patient-years in men and 217.0 (95% CI 32.8–3949.3) deaths per 100,000 patient-years in women; while age-standardized cancer-related mortality expected for the general Spanish population was 201.4 deaths per 100,000 patients-years in men (risk ratio = 1.71) and 96.2 deaths per 100,000 patients-years in women (risk ratio = 2.26). Patients with HF showed higher incidence rates of cancer diagnosis and cancer-related mortality than those expected for the general population. [Display omitted] [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of the Agtr1 gene leads to increased cell death in vitro and attenuates tumor progression in vivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells. [ABSTRACT FROM AUTHOR]

The role of a dysregulated renin-angiotensin system (RAS) in the pathogenesis of COVID-19 is well recognized. The imbalance between angiotensin II (Ang II) and Angiotensin 1-7 (Ang 1,7) caused by the interaction between SARS-CoV-2 and the angiotensin converting enzyme 2 (ACE 2) receptors exerts a pivotal role on the clinical picture and outcome of COVID-19. ACE 2 receptors are not the exclusive angiotensinases in nature. Other angiotensinases (PRCP, and POP) have the potential to limit the detrimental effects of the interactions between ACE 2 and the Spike proteins. In the cardiovascular disease continuum, ACE 2 activity tends to decrease, and POP/PRCP activity to increase, from the health status to advanced deterioration of the cardiovascular system. The failure of the counter-regulatory RAS axis during the acute phase of COVID-19 is characterized by a decrease of ACE 2 expression coupled to unchanged activity of other angiotensinases, therefore failing to limit the accumulation of Ang II. COVID-19 vaccines increase the endogenous synthesis of SARS-CoV-2 spike proteins. Once synthetized, the free-floating spike proteins circulate in the blood, interact with ACE 2 receptors and resemble the pathological features of SARS-CoV-2 ("Spike effect" of COVID-19 vaccines). It has been noted that an increased catalytic activity of POP/PRCP is typical in elderly individuals with comorbidities or previous cardiovascular events, but not in younger people. Thus, the adverse reactions to COVID-19 vaccination associated with Ang II accumulation are generally more common in younger and healthy subjects. Understanding the relationships between different mechanisms of Ang II cleavage and accumulation offers the opportunity to close the pathophysiological loop between the risk of progression to severe forms of COVID-19 and the potential adverse events of vaccination. [ABSTRACT FROM AUTHOR]

[Display omitted] • Neuromodulatory effects of ACE2 inhibitors were investigated in nerve terminals. • Two different types of small molecule ligands for selective ACE2 inhibition were tested. • EBC-36032 and EBC-36033 decreased exocytotic release of [3H]GABA. • Both inhibitors decreased the initial rate of uptake of L-[14C]glutamate and [3H]GABA. • Neurological side effects may be expected in therapeutic implementation. Here, neuromodulatory effects of selective angiotensin-converting enzyme 2 (ACE2) inhibitors were investigated. Two different types of small molecule ligands for ACE2 inhibition were selected using chemical genetic approach, they were synthesized using developed chemical method and tested using presynaptic rat brain nerve terminals (synaptosomes). EBC-36032 (1 µM) increased in a dose-dependent manner spontaneous and stimulated ROS generation in nerve terminals that was of non-mitochondrial origin. Another inhibitor EBC-36033 (MLN-4760) was inert regarding modulation of ROS generation. EBC-36032 and EBC-36033 (100 µM) did not modulate the exocytotic release of L-[14C]glutamate, whereas both inhibitors decreased the initial rate of uptake, but not accumulation (10 min) of L-[14C]glutamate by nerve terminals. EBC-36032 (100 µM) decreased the exocytotic release as well as the initial rate and accumulation of [3H]GABA by nerve terminals. EBC-36032 and EBC-36033 did not change the extracellular levels and transporter-mediated release of [3H]GABA and L-[14C]glutamate, and tonic leakage of [3H]GABA from nerve terminals. Therefore, synthesized selective ACE2 inhibitors decreased uptake of glutamate and GABA as well as exocytosis of GABA at the presynaptic level. The initial rate of glutamate uptake was the only parameter that was mitigated by both ACE2 inhibitors despite stereochemistry issues. In terms of ACE2-targeted antiviral/anti-SARS-CoV-2 and other therapies, novel ACE2 inhibitors should be checked on the subject of possible renin–angiotensin system (RAS)-independent neurological side effects. [ABSTRACT FROM AUTHOR]

• RAAS inhibition is a mainstay of the pharmacological treatment of HFrEF • In HFrEF, whenever possible, the use of ARNI should be preferred over ACE inhibitor • ARNI should be considered as first line therapy in de novo HFrEF patients • ARNI should be considered in HFmrEF, no definitive evidence support them in HFpEF Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community. [ABSTRACT FROM AUTHOR]

In this multicenter retrospective study, we studied the impact of the concurrent use of renin-angiotensin system inhibitors (RASi) on the outcomes of 229 metastatic renal cell carcinoma (mRCC) patients treated with immunecheckpoint inhibitors (ICI). The findings suggest that RASi could be repurposed to enhance outcomes with ICI in patients with mRCC, which may have a large global impact given their cost-efficacy. Background: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI. Methods: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR). Results: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034). Conclusions: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients. [ABSTRACT FROM AUTHOR]

The best treatment option for high-risk non muscle-invasive bladder cancer is BCG immunotherapy. In this study we looked for potential interaction between drugs with known immunomodulatory effects (angiotensin receptor blockers and ACE-inhibitors) and cancer recurrence in patients treated with BCG. Our results show a benefit in patients treated with angiotensin receptor blockers. Introduction: The gold standard treatment for high-risk NMIBC is BCG immunotherapy. Some studies suggested an immomodulatory effects for commonly used drugs (ie, ACE-I and ARBs). We aimed to determine whether these drugs impact the prognosis of patients with high-risk NMIBC treated with BCG. Materials and Methods: Retrospective analysis on 208 patients from a single academic center with primary high-risk NMIBC treated with transurethral resection followed by 6 weekly instillations of BCG and up to 12 monthly maintenance instillations. ARBs or ACE-I use at the time of treatment initiation was recorded. Inverse probability of treatment weighting (IPTW) was used to adjust for clinical and pathological covariates. IPTW-adjusted Kaplan-Meier curves and weighted Cox proportional hazards regression were used to compare 2-yr failure-free (2-yr FFS), failure-free (FFS), overall recurrence-free (RFS) and progression-free survival (PFS). Results: A total of 68 patients were on ACE-I, and 38 on ARBs and treatment respectively. At a median follow-up of 26 months, ACE-I treatment had no significant impact on cancer-related outcomes. Conversely, patients treated with ARBs experienced significant improvements in 2-yr FFS (HR 0.3; 0.1-0.9, P = .004), FFS (HR 0.4, 0.1-0.9, P = .005), and PFS (HR 0.001; < 0.001-0.001, P < .001). No significant impact was found for ARB use in RFS (HR 0.6; P = .09). Sensitivity analyses confirmed these results. Conclusions: our findings support a potential role of the angiotensin-renin system in bladder cancer development. We identified ARBs as potential beneficial drugs that seems to act in synergy with BCG-immunotherapy. [ABSTRACT FROM AUTHOR]

Angiotensin peptides (ANGs) play a central role in the renin–angiotensin–aldosterone system, rendering them interesting biomarkers associated with hypertension. Precise quantification of circulating ANGs holds the potential to assess the activity of angiotensin-converting enzyme (ACE), a key protease targeted by widely prescribed drugs, namely ACE inhibitors. This ability could pave the way for personalised medicine, offering insights into the prescription of inhibitors targeting either the proteases or the receptors within the system. Despite recent developments in liquid chromatography–mass spectrometry (LC-MS) methods for measuring circulating ANG concentrations, comprehensive stability studies of ANGs in human plasma are absent in the literature, raising concerns about the reliability of measured concentrations and their link to clinical conditions. To address this critical gap, we conducted an exhaustive evaluation of the pre-analytical stability of ANG1–10, ANG1–9, ANG1–8, ANG1–7, and ANG1–5. By employing surfactants to mitigate non-specific adsorption and a dedicated mix of protease inhibitors to limit protease activity, we established an MS-based assay for these five peptides. We used this method to quantify circulating concentrations of ANGs in the plasma of 11 healthy donors and 3 patients under kidney dialysis. Our findings revealed that ANG1–10 and ANG1–8 circulate at concentrations ranging from 1 to 10 pM in healthy subjects and exhibit a high degree of correlation. Notably, ANG1–9, ANG1–7, and ANG1–5 were undetectable in any of the 14 patients, despite a sub-picomolar limit of detection. This strikingly contrasts with the reference concentrations reported in the literature, which typically fall within the picomolar range. In light of these discrepancies, we strongly advocate for rigorous pre-analytical considerations and comprehensive stability studies to ensure reliable results. We emphasise the pivotal role of heightened pre-analytical awareness within the clinical chemistry community, and we hope for continued growth in this critical area. • A comprehensive stability study of angiotensin peptides (ANGs) is provided. • This method allows the detection of sub-picomolar ANGs concentrations. • ANGs are very sensitive to protease activity, resulting in fast metabolism. • We measured ANGs concentrations lower than previously reported in literature. [ABSTRACT FROM AUTHOR]

Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite optimal standard-of-care therapy and constitute the primary cause of death in intensive care units worldwide. Circulating biomarkers of septic shock severity may represent a clinically relevant approach to individualize those patients at risk for worse outcomes early in the course of the disease, which may facilitate early and more precise interventions to improve the clinical course. However, currently used septic shock biomarkers, including lactate, may be non-specific and have variable impact on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is likely an early event in septic shock, and studies suggest that an elevated level of renin, the early and committed step in the RAAS cascade, is a better predictor of worse outcomes in septic shock, including mortality, than the current standard-of-care measure of lactate. Despite a robust increase in renin, other elements of the RAAS, including endogenous levels of Ang II, may fail to sufficiently increase to maintain blood pressure, tissue perfusion, and protective immune responses in septic shock patients. We review the current clinical literature regarding the dysfunction of the RAAS in septic shock and potential therapeutic approaches to improve clinical outcomes. • We summarize clinical and experimental data on the possible dysfunction of the RAAS in septic shock. • RAAS dysfunction may reflect reduced ACE and Angiotensinogen but increased ACE2 and DPP3. • Septic shock may induce an imbalance in the RAAS with reduced Ang II but higher Ang-(1-7). • High circulating levels of active renin may be a predictor of disease severity in septic shock. [ABSTRACT FROM AUTHOR]

Heart failure (HF) has been increasing in morbidity and mortality worldwide, and one of the important causes of heart failure is myocardial infarction (MI), in which the coronary arteries are unable to provide sufficient blood flow to myocardial tissues, leading to necrosis and apoptosis, activation of inflammatory responses and neuroendocrine systems such as renin-angiotensin-aldosterone system (RAAS), generation of adverse ventricular remodeling, and finally the development of heart failure. In this paper, a drug-loaded polyphenol nanoparticles (ESaB NPs) containing active Angiotensin-converting enzyme inhibitor (ACEI) drugs enalaprilat and salvianolic acid B have been designed for the pathologic characteristics of acute MI. On this basis, a collagen/fucoidan hydrogel with good bioactivity and mechanical properties has been prepared, and the nanoparticles are incorporated into the aforementioned hydrogel to obtain a composite hydrogel (Gel-ESaB) with multiple synergistic therapeutic functions. The introduction of fucoidan can not only improve the mechanical strength and injectability of the collagen-based hydrogel, but also confer the collagen material with anticoagulant properties that are essential for future clinical applications as cardiovascular biomaterials. While providing mechanical support to the infarct site, the ESaB NPs delivered in situ to the infarct site play a key role in protecting myocardial tissue and restoring cardiac function through ROS scavenging, inflammation alleviation and tissue RAAS inhibitory ability. Both in vitro and in vivo experiments have confirmed the excellent therapeutic ability of Gel-ESaB in the treatment of MI and the prevention of HF after MI, which is expected to be an effective approach for MI treatment. [ABSTRACT FROM AUTHOR]

Overwhelming macrophage M1 polarization induced by malfunction of the renin–angiotensin–aldosterone system (RAAS) initiates inflammatory responses, which play a crucial role in various cardiovascular diseases. However, the underlying regulatory mechanism remains elusive. Here, we identified adaptor protein HIP-55 as a critical regulator of macrophage M1 polarization. The expression of HIP-55 was upregulated in M1 macrophage induced by Ang II. Overexpression of HIP-55 significantly promoted Ang II-induced macrophage M1 polarization, whereas genetic deletion of HIP-55 inhibited the Ang II-induced macrophage M1 polarization. Mechanistically, HIP-55 facilitated activator protein-1 (AP-1) complex activation induced by Ang II via promoting ERK1/2 and JNK phosphorylation. Moreover, blocking AP-1 complex activation can attenuate the function of HIP-55 in macrophage polarization. Collectively, our results reveal the role of HIP-55 in macrophage polarization and provide potential therapeutic insights for cardiovascular diseases associated with RAAS dysfunction. • Adaptor protein HIP-55 promotes macrophage M1 polarization triggered by RAAS overactivation. • HIP-55, a key bridge, links macrophage M1 polarization and RAAS overactivation. • Targeting HIP-55 presents a novel therapeutic strategy for preventing cardiovascular diseasesrelated to RAAS dysfunction. [ABSTRACT FROM AUTHOR]

Recent human and animal studies have delineated hypertension can develop in the earliest stage of life. A lack or excess of particular nutrients in the maternal diet may impact the expression of genes associated with BP, leading to an increased risk of hypertension in adulthood. Modulations in gene expression could be caused by epigenetic mechanisms through aberrant DNA methylation, histone modification, and microRNAs (miRNAs). Several molecular mechanisms for the developmental programming of hypertension, including oxidative stress, dysregulated nutrient-sensing signal, aberrant renin-angiotensin system, and dysbiotic gut microbiota have been associated with epigenetic programming. Conversely, maternal nutritional interventions such as amino acids, melatonin, polyphenols, resveratrol or short chain fatty acids may work as epigenetic modifiers to trigger protective epigenetic modifications and prevent offspring hypertension. We present a current perspective of maternal malnutrition that can cause fetal programming and the potential of epigenetic mechanisms lead to offspring hypertension. We also discuss the opportunities of dietary nutrients or nutraceuticals as epigenetic modifiers to counteract those adverse programming actions for hypertension prevention. The extent to which aberrant epigenetic changes can be reprogrammed or reversed by maternal dietary interventions in order to prevent human hypertension remains to be established. Continued research is necessary to evaluate the interaction between maternal malnutrition and epigenetic programming, as well as a greater focus on nutritional interventions for hypertension prevention towards their use in clinical translation. [ABSTRACT FROM AUTHOR]

[Display omitted] Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb‐derived natural compounds were found inhibiting AGT. 18β-glycyrrhetinic acid (18βGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18βGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18βGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18βGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18βGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation. [ABSTRACT FROM AUTHOR]

E-cadherin plays a critical role in preserving cell-cell adhesion and tissue integrity, and its reduced expression is a hallmark feature of the epithelial-mesenchymal transition (EMT) associated with cancer metastasis. This paper explores signaling pathways, including Snail family transcriptional repressor (Snail), Mitogen-activated protein kinase (MAPK), Store-operated calcium entry (SOCE), Transforming growth factor (TGF-β), Janus kinase/signal transducers and activators of transcription (JAK/STAT), Wingless-related integration site (Wnt), and Renin angiotensin system (RAS), elucidating their functions in regulating E-cadherin levels and controlling cell migration and proliferation. Also, regulation of E-cadherin signaling pathways by various dietary components is explored. This comprehensive review presents the critical role of E-cadherin and its associated pathways in various diseases, particularly cancer and cardiovascular conditions. Additionally, the article discusses the influence of dietary components like antioxidants, polyphenols, and herbs on E-cadherin pathways, offering potential pathways for modulating cell migration and proliferation in chronic diseases. It emphasizes the potential for therapeutic interventions targeting these pathways and suggests the significance of considering dietary factors in disease prevention and treatment strategies. • Loss of E-cadherin is an essential element of invasion and metastasis. • E-cadherin and related pathways including Snail, MAPK, SOCE, TGF-β, JAK/STAT, Wnt, and RAS regulate migration and proliferation. • Dietary components influence the E-cadherin pathways and interaction. [ABSTRACT FROM AUTHOR]