Hypotensive effect of potent angiotensin-I-converting enzyme inhibitory peptides from corn gluten meal hydrolysate: Gastrointestinal digestion and transepithelial transportation modifications.

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (Ki) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide.

Antihypertensive medications and dementia in older adults with hypertension.

Background: Studies on middle-aged or individuals with cognitive or cardiovascular impairments, have established that intensive blood pressure (BP) control reduces cognitive decline risk. However, uncertainty exists on differential effects between antihypertensive medications (AHM) classes on this risk, independent of BP-lowering efficacy, particularly in community-dwelling hypertensive older adults. Methods: A post-hoc analysis of the ASPREE study, a randomized trial of low-dose aspirin in adults aged 70+ years (65+ if US minorities) without baseline dementia, and followed for two years post-trial. Cox proportional-hazards regression models were used to estimate associations between baseline and time-varying AHM exposure and incident dementia (an adjudicated primary trial endpoint), in participants with baseline hypertension. Subgroup analyses included prespecified factors, APO ε4 carrier status and monotherapy AHM use. Results: Most hypertensive participants (9,843/13,916; 70.7%) used AHMs. Overall, 'any' AHM use was not associated with lower incident dementia risk, compared with untreated participants (HR 0.84, 95%CI 0.70-1.02, p=0.08), but risk was decreased when angiotensin receptor blockers (ARBs) were included (HR 0.73, 95%CI 0.59-0.92, p=0.007). ARBs and ß-blockers decreased dementia risk, whereas angiotensin-converting enzyme inhibitors (ACEIs) and diuretics increased risk. There was no association with RAS modulating or blood-brain-barrier crossing AHMs on dementia risk. Conclusions: Overall, AHM exposure in hypertensive older adults was not associated with decreased dementia risk, however, specific AHM classes were with risk direction determined by class; ARBs and ß-blockers were superior to ACEIs and other classes in decreasing risk. Our findings emphasize the importance of considering effects beyond BP-lowering efficacy when choosing AHM in older adults.

Antihypertensive Effects of Lindera erythrocarpa Makino via NO/cGMP Pathway and Ca2+ and K+ Channels.

Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.

PANoptosis is a Prominent Cell Death Feature in Thoracic Aortic Aneurysm or Dissection.

Thoracic aortic aneurysm and dissection (TAAD) is a devastating macrovascular disease, and its pathogenic mechanisms have not been well clarified. This study aimed to investigate the role of PANoptosis, which is newly defined programmed cell death (PCD) and characterized by pyroptosis, apoptosis, and necroptosis, in the pathogenesis of TAAD. We found that the expression of initiator factor Z-DNA binding protein 1 (ZBP1) and PANoptosis-related genes were upregulated in the ß-aminopropionitrile (BAPN)+Angiotensin II (Ang II)-induced TAAD mice. Ang II stimuli enhanced the expression of ZBP1, promoted the generation of bioactive GSDMD (Gasdermin D) fragments, the cleavage of Caspase 3, and increased the phosphorylation of mixed lineage kinase domain-like pseudokinase (MLKL ) in human aortic vascular smooth muscle cells (HASMCs), indicating the activation of hallmarks for PANoptosis. Moreover, ZBP1-mediated PANoptosis occurs in the aortic tissues of TAAD patients. These results highlight the significant role of PANoptosis in TAAD pathogenesis, suggesting ZBP1 and other PANoptosis-related genes as potential therapeutic targets for this condition.

Cardiovascular and Renal Treatment in Heart Failure Patients with Hyperkalemia or High Risk of Hyperkalemia: Rationale and Design of the CARE-HK in HF Registry.

BACKGROUND: Despite guideline recommendations, many patients with heart failure (HF) do not receive target doses of renin-angiotensin-aldosterone system inhibitors (RAASis) in clinical practice due, in part, to concerns about hyperkalemia (HK). METHODS AND RESULTS: This non-interventional, multinational, multicenter registry (NCT04864795; 111 sites in Europe and the USA) enrolled 2,558 eligible adults with chronic HF (mostly with reduced ejection fraction [HFrEF]). Eligibility criteria included use of angiotensin-converting-enzyme inhibitor / angiotensin-II receptor blocker / angiotensin-receptor-neprilysin inhibitor, candidate for or treatment with mineralocorticoid receptor antagonist, and increased risk of HK (eg, current serum potassium >5.0 mmol/L], history of HK in the previous 24 months, or estimated glomerular filtration rate <45 mL/min/1.73 m2). Information on RAASi and other guideline-recommended therapies was collected retrospectively and prospectively (≥6 months). Patients were followed according to local clinical practice, without study-specific visits or interventions. The main objectives were to characterize RAASi treatment patterns compared with guideline recommendations, describe RAASi modifications following episodes of HK, and describe RAASi treatment in patients treated with patiromer. Baseline characteristics for the first 1,000 patients are presented. CONCLUSIONS: CARE-HK is a multinational prospective HF registry designed to report on the management and outcomes of patients with HF at high risk for HK in routine clinical practice.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

Radiotracers for Molecular Imaging of Angiotensin-Converting Enzyme 2.

Angiotensin-converting enzymes (ACE) are well-known for their roles in both blood pressure regulation via the renin-angiotensin system as well as functions in fertility, immunity, hematopoiesis, and many others. The two main isoforms of ACE include ACE and ACE-2 (ACE2). Both isoforms have similar structures and mediate numerous effects on the cardiovascular system. Most remarkably, ACE2 serves as an entry receptor for SARS-CoV-2. Understanding the interaction between the virus and ACE2 is vital to combating the disease and preventing a similar pandemic in the future. Noninvasive imaging techniques such as positron emission tomography and single photon emission computed tomography could noninvasively and quantitatively assess in vivo ACE2 expression levels. ACE2-targeted imaging can be used as a valuable tool to better understand the mechanism of the infection process and the potential roles of ACE2 in homeostasis and related diseases. Together, this information can aid in the identification of potential therapeutic drugs for infectious diseases, cancer, and many ACE2-related diseases. The present review summarized the state-of-the-art radiotracers for ACE2 imaging, including their chemical design, pharmacological properties, radiochemistry, as well as preclinical and human molecular imaging findings. We also discussed the advantages and limitations of the currently developed ACE2-specific radiotracers.

ACE2 Knockout Mice Are Resistant to High-Fat Diet-Induced Obesity in an Age-Dependent Manner.

Angiotensin converting enzyme 2 (ACE2) presents pleiotropic actions. It hydrolyzes angiotensin I (AngI) and angiotensin II (AngII) into angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), respectively, as well as participates in tryptophan uptake in the gut and in COVID-19 infection. Our aim was to investigate the metabolic effect of ACE2 deletion in young adults and elderly mice under conditions of high calorie intake. Male C57Bl/6 (WT) and ACE2-deficient (ACE2-/y) mice were analyzed at the age of 6 and 12 months under standard diet (StD) and high-fat diet (HFD). Under StD, ACE2-/y showed lower body weight and fat depots, improved glucose tolerance, enhanced insulin sensitivity, higher adiponectin, and lower leptin levels compared to WT. This difference was even more pronounced after HFD in 6-month-old mice, but, interestingly, it was blunted at the age of 12 months. ACE2-/y presented a decrease in adipocyte diameter and lipolysis, which reflected in the upregulation of lipid metabolism in white adipose tissue through the increased expression of genes involved in lipid regulation. Under HFD, both food intake and total energy expenditure were decreased in 6-month-old ACE2-/y mice, accompanied by an increase in liquid intake, compared to WT mice, fed either StD or HFD. Thus, ACE2-/y mice are less susceptible to HFD-induced obesity in an age-dependent manner, as well as represent an excellent animal model of human lipodystrophy and a tool to investigate new treatments.

A Possible Link between Cell Plasticity and Renin Expression in the Collecting Duct: A Narrative Review.

The hormone renin is produced in the kidney by the juxtaglomerular cells. It is the rate-limiting factor in the circulating renin-angiotensin-aldosterone system (RAAS), which contributes to electrolyte, water, and blood pressure homeostasis. In the kidneys, the distal tubule and the collecting duct are the key target segments for RAAS. The collecting duct is important for urine production and also for salt, water, and acid-base homeostasis. The critical functional role of the collecting duct is mediated by the principal and the intercalated cells and is regulated by different hormones like aldosterone and vasopressin. The collecting duct is not only a target for hormones but also a place of hormone production. It is accepted that renin is produced in the collecting duct at a low level. Several studies have described that the cells in the collecting duct exhibit plasticity properties because the ratio of principal to intercalated cells can change under specific circumstances. This narrative review focuses on two aspects of the collecting duct that remain somehow aside from mainstream research, namely the cell plasticity and the renin expression. We discuss the link between these collecting duct features, which we see as a promising area for future research given recent findings.

Transcriptome sequencing analysis reveals the molecular regulatory mechanism of myocardial hypertrophy induced by angiotensin II.

The pathogenesis of myocardial hypertrophy remains incompletely understood, highlighting the critical need for in-depth investigation into its pathogenesis and pathophysiology to develop innovative strategies for preventing and treating heart diseases. In this study, a model of angiotensin II (Ang II)-induced myocardial hypertrophy was established using subcutaneous administration with a micropump. Echocardiography, wheat germ agglutinin staining, and western blot analysis were used to evaluate the myocardial hypertrophy model after 5, 10, and 15 days of Ang II treatment. RNA-seq was employed to analyze the differential expression profile of mRNA, followed by bioinformatics analysis. Subsequently, the anti-inflammatory drug meloxicam was utilized to explore its impact on cardiac hypertrophy in mice. The findings demonstrated that mice developed myocardial hypertrophy following subcutaneous administration of Ang II. Transcriptomic analysis revealed significant changes in gene expression in the myocardium induced by Ang II, with the most pronounced differences observed at day 10. Functional analysis and verification of differentially expressed genes indicated that Ang II triggered an inflammatory response in the myocardium, leading to up-regulation of genes associated with fibrosis and apoptosis while decreasing energy metabolism; alterations were also observed in genes related to oxidative stress and calcium ion binding. Treatment with meloxicam improved Ang II-induced myocardial hypertrophy. This study not only elucidated the molecular regulatory mechanism underlying mouse myocardial hypertrophy at a transcriptional level but also provided new insights into clinical prevention and treatment strategies for cardiac diseases such as dilated cardiomyopathy and heart failure.

Rational design, synthesis and pharmacological characterization of novel aminopeptidase A inhibitors.

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

Angiotensin converting enzyme (ACE) inhibitory peptide from the tuna (Thunnus thynnus) muscle: Screening, interaction mechanism and stability.

In this study, the purpose was to screen novel angiotensin converting enzyme inhibitory peptides (ACEIPs) from tuna muscle taking two-steps enzymatic hydrolysis (Neutrase and Alkaline). Following isolation and purification by ultrafiltration, the Sephadex G-15 gel chromatography and reversed-phase high-performance liquid chromatography based on active-guide, the amino acid sequence was identified using Q-Orbitrap-MS/MS. Five peptides were chose synthesized based on the in silico screening methods. Among these, the two novel ACEIPs LTGCP and YPKP showed better inhibitory ability, and their corresponding IC50 values were 64.3 µM and 139.6 µM. Subsequently, the interaction mechanism of the best active peptide (LTGCP) against ACE was investigated by inhibitory pattern, molecular docking and molecular dynamic simulation. The result displayed that LTGCP was a mix-type inhibitor against ACE from the Lineweaver-Burk plots. LTGCP formed seven hydrogen bonds based on the molecular docking and the binding energy was -7.29 kcal/mol. LTGCP formed a stability complex with ACE based on the molecular dynamic simulation. Besides, LTGCP exhibited good stability in various temperature, pH and gastrointestinal digestion. Finally, the 0.125 mM âˆ¼ 1.0 mM LTGCP exhibited no-toxic for Caco-2 cell. In summary, these findings showed that tuna was a good material to prepare ACEIPs and LTGCP may be the good potential antihypertensive drug or nutraceuticals.

Role of Local Angiotensin II Signaling in Bladder Function.

Local renin-angiotensin signaling is present within various organ systems of the body. Angiotensin II signaling acts as a crucial mechanism of the renin-angiotensin signaling system. In this manuscript, we review current literature regarding local angiotensin II signaling in the urinary bladder. Our interest in this pathway is due to its potential role in interstitial cystitis/bladder pain syndrome and other bladder diseases, which are chronic in nature and negatively affect patients' quality of life. Current treatments for bladder diseases are generally ineffective due to our lack of understanding of their pathophysiology. We evaluate literature investigating angiotensin II signaling in the bladder across several perspectives, including local expression and production, functional properties, tissue morphology, and clinical implications. Further, we identify gaps in knowledge and suggest areas where we can improve our understanding of angiotensin II signaling in the bladder.

MAS RECEPTOR BLOCKADE IMPAIRS EXERCISE-INDUCED CARDIAC HYPERTROPHY.

Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes.

Paricalcitol prevents renal tubular injury induced by ischemia-reperfusion: Role of oxidative stress, inflammation and AT1R.

The vitamin D receptor (VDR) is associated with antioxidative and anti-inflammatory effects and modulation of the renin-angiotensin-aldosterone system. This study evaluated whether VDR agonist paricalcitol protects renal ischemia-reperfusion (IR) induced tubular injury in rats by evaluating: 1) ATP-dependent tubular Na+ transport; 2) renal redox signaling; 3) renal content of proinflammatory cytokines TNF-α and IL-6; and 4) renal content of renin and angiotensin II receptor type 1 (AT1R). Paricalcitol prevented IR-induced tubular injury, evidenced by the prevention of histopathological changes and renal fibrosis with preservation of the activity of ATP-dependent Na+ transporters in the renal cortex. Paricalcitol decreased renal oxidative stress by reducing NADPH oxidase activity and increasing catalase. Paricalcitol also decreased the renal content of TNF-α, IL-6, and AT1R. The NADPH oxidase inhibitor apocynin did not present additive protection to paricalcitol-induced effects. The protective effects of paricalcitol on tubular injury induced by renal IR may dependent on the modulation of redox and proinflammatory signaling and renal angiotensin II/AT1R signaling.

Association of the protective effect of telmisartan on hearing loss among patients with hypertension.

Aim: Hearing loss, affecting a significant portion of the global population, is prevented with peroxisome proliferator-activated receptor γ agonism. Understanding potential protective treatments is crucial for public health. We examine the effect of telmisartan, an antihypertensive drug and partial peroxisome proliferator-activated receptor γ agonist, on hearing loss in patients with hypertension. Method and results: This retrospective cohort analysis used data from the OMOP Common Data Model database, encompassing information from three tertiary institutions in South Korea. The study included a substantial sample size of 860,103 people diagnosed with hypertension. The study included individuals who had been medically diagnosed with hypertension and had been prescribed antihypertensive drugs, including telmisartan. The study design was established to evaluate the comparative effects of telmisartan and other hypertension medications on hearing loss. We used propensity score matching (PSM) to create a balanced cohort, reducing potential biases between the telmisartan and non-telmisartan groups. From the initial 860,103 patients with hypertension, a propensity score matched cohort was derived from 20,010 patients, with 2,193 in the telmisartan group. After PSM, lower incidence of total hearing loss was observed in the telmisartan group compared to the non-telmisartan group during the 3-year follow-up (0.5% vs. 1.5%, log-rank p = 0.005). In subgroup analysis, this study showed consistent results that lower incidence of total hearing loss was higher in the telmisartan group than in the non-telmisartan group. Conclusion: Telmisartan was associated with reducing certain types of hearing loss in patients with hypertension. Further research is needed to confirm these findings and understand the mechanisms.

Renin angiotensin system inhibitors and outcome in patients with Takotsubo syndrome: a propensity score analysis of the GEIST registry.

BACKGROUND: Few data are available on long-term drug therapy and its potential prognostic impact after Takotsubo syndrome (TTS). Aim of the study is to evaluate clinical characteristics and long-term outcome of TTS patients on Renin Angiotensin system inhibitors (RASi). METHODS: TTS patients were enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry. Median follow-up was 31 (Interquartile range 12-56) months. Comparison of RASi treated vs. untreated patients was performed within the overall population and after 1:1 propensity score matching for age, sex, comorbidities, type of trigger and in-hospital complications. REGISTRATION: clinicaltrials.gov, NCT04361994, https://clinicaltrials.gov/study/NCT04361994 RESULTS: Of the 2453 TTS patients discharged alive, 1683 (68%) received RASi therapy. Patients with RASi were older (age 71±11 vs 69±13 years, p=0.01), with higher prevalence of hypertension (74%vs53%, p<0.01) and diabetes (19%vs15%, p=0.01), higher admission left ventricular ejection fraction (LVEF) (41±11% vs 39±12%, p<0.01) and lower rates of in-hospital complications (18.9% vs 29.6%, p<0.01). At multivariable analysis, RASi therapy at discharge was independently associated with lower mortality (HR 0.63, 95%CI 0.45-0.87, p<0.01). Survival analysis showed that at long term, patients treated with RASi had lower mortality rates in the overall cohort (log-rank p=0.001). However, this benefit was not found among patients treated with RASi in the matched cohort (log-rank p=0.168). Potential survival benefit of RASi were present, both in the overall and matched cohort, in two subgroups: patients with admission LVEF ≤40% (HR 0.54 95%CI 0.38-0.78, p=0.001; HR 0.59, 95%CI 0.37-0.95, p=0.030) and diabetes (HR 0.41, 95%CI 0.23-0.73, p= 0.002; HR 0.41, 95%CI 0.21-0.82, p=0.011). CONCLUSIONS: Long-term therapy with RASi after a TTS episode was not associated with lower mortality rates at propensity score analysis. However, potential survival benefit can be found among patients with admission LVEF ≤40% or diabetes.

The angiotensin-(1-7)/MasR axis improves pneumonia caused by Pseudomonas aeruginosa: Extending the therapeutic window for antibiotic therapy.

Pseudomonas aeruginosa is a frequent cause of antimicrobial-resistant hospital-acquired pneumonia, especially in critically ill patients. Inflammation triggered by P. aeruginosa infection is necessary for bacterial clearance but must be spatially and temporally regulated to prevent further tissue damage and bacterial dissemination. Emerging data have shed light on the pro-resolving actions of angiotensin-(1-7) [Ang-(1-7)] signaling through the G protein-coupled receptor Mas (MasR) during infections. Herein, we investigated the role of the Ang-(1-7)/Mas axis in pneumonia caused by P. aeruginosa by using genetic and pharmacological approach and found that Mas receptor-deficient animals developed a more severe form of pneumonia showing higher neutrophilic infiltration into the airways, bacterial load, cytokines, and chemokines production and more severe pulmonary damage. Conversely, treatment of pseudomonas-infected mice with Ang-(1-7) was able to decrease neutrophilic infiltration in airways and lungs, local and systemic levels of pro-inflammatory cytokines and chemokines, and increase the efferocytosis rates, mitigating lung damage/dysfunction caused by infection. Notably, the therapeutic association of Ang-(1-7) with antibiotics improved the survival rates of mice subjected to lethal inoculum of P. aeruginosa, extending the therapeutic window for imipenem. Mechanistically, Ang-(1-7) increased phagocytosis of bacteria by neutrophils and macrophages to accelerate pathogen clearance. Altogether, harnessing the Ang-(1-7) pathway during infection is a potential strategy for the development of host-directed therapies to promote mechanisms of resistance and resilience to pneumonia.

Impact of inhibition of the renin-angiotensin system on early cardiac and renal abnormalities in Sprague Dawley rats fed short-term high fructose plus high salt diet.

Introduction: The combination of a high fructose and high salt diet typical of western diet induces high blood pressure, aortic stiffening, left ventricular (LV) diastolic dysfunction and impaired renal function in rodents. Despite an activated renin-angiotensin system (RAS) in rats fed high fructose and high salt, acute inhibition of the RAS pathway does not improve cardiac and vascular parameters. It may well be that longer term treatment is required to permit remodeling and improve cardiovascular function. Thus, we hypothesized that chronic RAS inhibition fructose+high salt-fed rats to restore blood pressure (BP) to levels similar to glucose plus normal salt-fed controls will improve cardiorenal function and histopathology. Methods: Male and female Sprague Dawley rats monitored by hemodynamic telemetry were fed 0.4% NaCl chow during baseline, then changed to chow containing either 20% glucose+0.4% NaCl (G) or 20% fructose+4% NaCl (F) and treated with vehicle, enalapril (Enal, 4 mg/kg/d) or losartan (Los, 8 mg/kg/d) by osmotic minipump for 25-26 days. Results: BP was elevated in the fructose+high salt groups of both sexes (P < 0.05) and restored to control levels by Enal or Los. Pulse wave velocity (PWV) was lower in female F+Los rats and cardiac output higher in female F+Enal rats. GFR was not changed by diet or treatment. Fructose+high salt groups of both sexes displayed higher albuminuria that was decreased by Enal in male rats. Cardiac fibrosis and mesangial hypercellularity were greater in fructose+high salt-fed rats of both sexes and improved with either Los or Enal. Discussion: Thus, inhibition of the RAS improves early changes in cardiac and renal histopathology in both sexes and albuminuria in male rats fed high fructose and high salt diet. Functional improvements in cardiorenal parameters may require longer treatment.

Cardio-Oncology's Modern Approaches to Prevent Doxorubicin-Induced Cardiotoxicity: A Systematic Review.

Advances in the field of oncology have led to the advent of doxorubicin (DOX), an anthracycline chemotherapeutic agent, through which cancer survival rates have remarkably improved. There has, however, been a rise in adverse effects from the use of DOX, most notably cardiotoxicity. DOX-induced cardiotoxicity is thought to arise through the generation of reactive oxygen species (ROS), causing mitochondrial dysfunction in the cardiomyocytes. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards and focused on cancer patients undergoing DOX therapy. The research question addressed interventions aimed at preventing DOX-induced cardiotoxicity. Google Scholar, PubMed, and ScienceDirect databases were used to conduct a systematic search. Next, screening was carried out by reviewing the title and abstract of various articles to exclude irrelevant studies, followed by the retrieval of full-text articles. Scale for the assessment of narrative review articles 2 (SANRA 2) for narrative reviews, a measurement tool to assess systematic reviews (AMSTAR) checklist for systematic reviews, and the Cochrane risk of bias tool for randomized controlled trials (RCTs) were the tools employed for quality assessment. This systematic review provides convincing evidence about preventive interventions to counteract DOX-induced cardiotoxicity. Primary prevention strategies against DOX-induced cardiotoxicity include pharmacological and non-pharmacological measures. Dexrazoxane reduces cardiotoxicity without therapeutic compromise. Beta-blockers showed mixed results in preserving cardiac function. The research on renin-angiotensin-aldosterone system (RAAS) inhibitors suggests that most of these agents can reduce the risk of DOX-induced cardiotoxicity. The liposomal formulation of DOX decreases cardiotoxicity without sacrificing effectiveness. Chemotherapy regimens should be supplemented with cardioprotective medications to increase therapeutic efficacy and lower cardiac risks. Exercise is an essential non-pharmacological strategy for decreasing DOX-induced cardiotoxicity. It acts by lowering oxidative stress, maintaining mitochondrial function, and averting apoptosis. Other non-pharmacological interventions through antioxidative, anti-apoptotic, and mitochondrial protective mechanisms, such as resveratrol, vitamin E, curcumin, and visnagin, show promise in lowering DOX-induced cardiotoxicity and may be useful as supplementary therapy during cancer treatment. In conclusion, this review highlights the need for a multimodal strategy that incorporates different tactics, as well as the need for additional research and strong clinical trials, with the ultimate goal of protecting cardiac health in patients receiving chemotherapy with DOX.