Cerebral small vessel injury in mice with damage to ACE2-expressing cerebral vascular endothelial cells and post COVID-19 patients.

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS-CoV-2. METHODS: We specifically induced injury to ACE2-expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single-center cohort of COVID-19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements. RESULTS: Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2-expressing CVECs, and COVID-19 survivors. These CSVD-like manifestations persist for at least 7 months post-recovery from COVID-19. DISCUSSION: Our findings suggest that SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS-CoV-2-mediated cerebral endothelial injury throughout infection and convalescence. HIGHLIGHTS: Cerebral small vessel disease-associated changes were observed after targeted damage to angiotensin-converting enzyme 2-expressing cerebral vascular endothelial cells. SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS-CoV-2-induced cerebral endothelial damage during infection and recovery.

Effect of different single and combined antihypertensive drug regimens on the mortality of critical care patients.

Objective: To investigate the effect of different single and combined pre-admission antihypertensive drug regimens on the prognosis of critically ill patients. Methods: We performed a retrospective cohort study using data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. All initial ICU admission records of patients with hypertension and previous antihypertensive exposure before ICU admission were included. Our primary outcome was 90-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance the distribution of baseline characteristics. Logistic regression analysis and subgroup analysis were performed to determine the independent effect of different single and combined antihypertensive drug regimens on 90-day mortality. Results: A total of 13,142 patients were included in the final analysis. The 90-day mortality rate in the combined groups is lower than that in the single therapy group (10.94% vs 11.12%), but no statistical significance was found in the original cohort (p = 0.742). After adjustment for potential confounders, the significantly decreased 90-day mortality rate was found in the combined groups (10.78% vs 12.65%, p = 0.004 in PSM; 10.34% vs 11.90%, p = 0.007). Patients who were exposed to either ACEIs or ARBs had a better prognosis than those not exposed (7.19% vs 17.08%, p < 0.001 in single antihypertensive groups; 8.14% vs18.91%, p < 0.001 in combined antihypertensive groups). The results keep robustness in the PSM and IPTW cohorts. In the logistic regression model analysis, combined therapy was associated with a 12%-20% reduced risk of 90-day death after adjusting potential confounders (OR 0.80-0.88, all p < 0.05), while exposure to ACEIs or ARBs was associated with the decreased risk of 90-day death by 52%-62% (OR 0.38-0.48, all p < 0.001) and 40%-62% (OR 0.38-0.60, all p < 0.001) in the single and combined therapy groups, respectively. The results were still robust to subgroup analysis. Conclusions: Pre-admission combined antihypertensive therapy is associated with a significantly lower risk of death than exposure to single antihypertensives in critically ill patients. Meanwhile, either ACEIs or ARBs seem to be the optimal candidates for both single and combined therapy. Further high-quality trials are needed to confirm our findings.

Investigation of cardiorenal outcomes and incidence of genitourinary tract infection after combined SGLT2 inhibitor and ACEI/ARB use in patients with chronic kidney disease stages 3-5: A real-world retrospective cohort study in Taiwan.

Background: Sodium‒glucose cotransporter-2 (SGLT2) inhibitors offer glycaemic and cardiorenal benefits in the early stage of chronic kidney disease (CKD). However, the use of SGLT2 inhibitors may increase the risk of genitourinary tract infection (GUTI). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may also cause deterioration of kidney function. The long-term follow-up of cardiorenal outcomes and GUTI incidence in patients with advanced CKD receiving SGLT2 inhibitors combined with ACEIs/ARBs should be further investigated. Methods: We analysed data from 5,503 patients in Taiwan's Taipei Medical University Research Database (2016-2020) who were part of a pre-end-stage renal disease (ESRD) program (CKD stages 3-5) and received ACEIs/ARBs. SGLT2 inhibitor users were matched 1:4 with nonusers on the basis of sex, CKD, and program entry duration. Results: The final cohort included 205 SGLT2 inhibitor users and 820 nonusers. SGLT2 inhibitor users experienced a significant reduction in ESRD/dialysis risk (aHR = 0.35, 95% CI = 0.190.67), and SGLT2 inhibitor use was not significantly associated with acute kidney injury or acute kidney disease risk. Among SGLT2 inhibitor users, those with a history of cardiovascular disease (CVD) had greater CVD rates. Conversely, those without a CVD history had lower rates of congestive heart failure, arrhythmia, acute pulmonary oedema, and acute myocardial infarction, although the differences were not statistically significant. Notably, SGLT2 inhibitor usage was associated with a greater GUTI incidence (aHR = 1.78, 95% CI = 1.122.84) shortly after initiation, irrespective of prior GUTI history status. Conclusion: Among patients with CKD stages 3-5, SGLT2 inhibitor use was linked to increased GUTI incidence, but it also significantly reduced the ESRD/dialysis risk without an episodic AKI or AKD risk. Clinical physicians should consider a personalized medicine approach by balancing GUTI episodes and cardiorenal outcomes for advanced CKD patients receiving SGLT2 inhibitors.

Mortality and Health Outcomes among Sarcoidosis Patients Treated with Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

BACKGROUND: Sarcoidosis is a multisystem inflammatory disease where management and outcomes can vary widely. The renin-angiotensin-aldosterone system (RAAS) has been implicated in its pathogenesis, yet the impact of RAAS modulators on health outcomes in sarcoidosis remains poorly understood. RESEARCH QUESTION: How do pharmacological modulators of RAAS affect health outcomes in patients diagnosed with sarcoidosis? STUDY DESIGN AND METHODS: We conducted a large multicenter investigation using the TriNetX Research Network database. Patients included in our study were individuals diagnosed with sarcoidosis and prescribed either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). All cohorts were matched for important covariates, and outcomes measured included mortality, cardiac and respiratory outcomes, and sepsis rates following sarcoidosis diagnosis. RESULTS: We observed an increased mortality risk among sarcoidosis patients prescribed ACE inhibitors compared to patients prescribed ARB therapies. Furthermore, sarcoidosis patients prescribed ACE inhibitors had worse cardiac and respiratory outcomes, and increased sepsis rates compared to the ARB cohort. INTERPRETATION: Our findings suggest that ACE inhibitors and ARB's have divergent effects on outcomes in sarcoidosis patients. These findings highlight the potential pathogenic role of RAAS signaling in this disease and underscore the importance of carefully selecting RAAS modulators for individuals with sarcoidosis.

Discovery of a novel nanomolar angiotensin-I converting enzyme inhibitory peptide with unusual binding mechanisms derived from Chlorella pyrenoidosa.

Chlorella pyrenoidosa (C. pyrenoidosa) has been cultivated in large quantities and proven to be antihypertensive when consumed orally. However, the antihypertensive peptides derived from C. pyrenoidosa remains scarce. In this study, trypsin was chosen to prepare the hydrolysate of C. pyrenoidosa, which was then fractionated by column chromatography. And ninety-nine peptides were identified by LC-MS/MS, after which 10 peptides were chosen by docking-based virtual screening and demonstrated their ability to inhibit ACE. Among them, LVAKA (LV-5) had the lowest IC50 (26.66 µM). LV-5, LKKAP, and PGLRP were identified as non-competitive ACE inhibitory peptides with significant stability under extreme pH and high temperatures conditions. Both in silico and in-vitro simulated gastrointestinal digestion revealed that these three peptides could release ACE inhibitory peptide fragments upon digestion. Sequence optimization of LV-5 led to the discovery of LRAKA (LR-5), which was identified as a novel nanomolar ACE peptide with an IC50 of 350 nM in-vitro and a potent antihypertensive peptide in-vivo. Moreover, molecular dynamic simulation indicated that LR-5 interacted with an unconventional binding site on ACE. These findings underscore the potential of Chlorella as a source of antihypertensive peptides and suggest a promising future for the use of Chlorella-derived peptides in hypertension management.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers are Associated with Improved Amputation Free Survival in Chronic Limb-Threatening Ischemia.

BACKGROUND: In the Heart Outcomes Prevention Evaluation (HOPE) study, investigators found that ramipril was associated with improved survival as well as decreased MI and stroke rates in patients with peripheral arterial disease. Nonetheless, their effect on chronic limb-threatening ischemia (CLTI)-specific outcomes is unclear. We aim to assess the effect of ACEIs/ARBs on amputation-free survival in CLTI patients undergoing peripheral vascular intervention (PVI) in a Medicare-linked database. METHODS: Patients undergoing PVI in the VQI-VISION database were included. Primary outcome included amputation-free survival. Kaplan Meier survival and multivariable Cox regression analyses were used to assess one-year outcomes. RESULTS: A total of 34,284 patients were included, and 46.3% of whom were discharged on ACEIs/ARBs. Patients discharged on ACEIs/ARBs were more likely to be smokers, diabetics, and hypertensive. They were also more likely to present with rest pain. The overall one-year survival for patients on ACEIs/ARBs vs those who are not was (79.1% vs 69.4%, P<0.001). Freedom from amputation was 87.8% for patients on ACEIs/ARBs vs 84.2% for those who were not (P<0.001). Amputation-free survival was 70.5% vs 59.5% for ACEIs/ARBs vs no ACEIs/ARBs (P<0.001). After adjusting for potential confounders, ACEIs/ARBs use was associated with lower one-year mortality (HR: 0.77, 95%CI (0.7-0.8), P<0.001), amputation (HR: 0.89, 95%CI (0.8-0.9), P<0.001), and amputation or death (HR: 0.79, 95%CI (0.76-0.8), P<0.001). CONCLUSIONS: ACEIs/ARBs were independently associated with lower amputation, improved survival, and amputation-free survival at one year in CLTI patients undergoing PVI. The fact that more than half the patients were not discharged on these medications presents an area for potential quality improvement.

Serum angiotensin-converting enzyme has low diagnostic value for pediatric sarcoid uveitis.

PURPOSE: Sarcoid uveitis is rare in the pediatric population. Early diagnosis is challenging and is crucial, due to more severe complications. Diagnosis relies on various criteria, including elevated angiotensin-converting enzyme (ACE) levels. The objective of this study was to evaluate the diagnostic value of serum ACE levels in the diagnosis of pediatric sarcoid uveitis. METHODS: This was an observational retrospective multicenter study of chronic, severe pediatric uveitis between 2013 and 2019 in two French tertiary referral centers. RESULTS: An ACE assay result was available for 105 patients. Nine patients were diagnosed with sarcoid uveitis. The diagnostic values were as follows: sensitivity=22.2%, specificity=87.5%, positive predictive value=14.3%, negative predictive value=92.3%, positive likelihood ratio=1.8, and negative likelihood ratio=0.9. CONCLUSION: The diagnostic performance of ACE in pediatric sarcoid uveitis was found to be poor. NPV exceeded 90% but was based on a significant number of false negatives, indicating a high risk of misdiagnosis. Likelihood ratios confirmed the limited diagnostic value of ACE. Considering age groups and clinical manifestations may enhance precision but requires larger studies. Serum ACE used as a diagnostic marker in pediatric sarcoid uveitis warrants caution and should be interpreted alongside other factors.

Indole alleviates nonalcoholic fatty liver disease in an ACE2-dependent manner.

Indole is a microbial metabolite produced by the gut microbiota through the degradation of dietary tryptophan, known for its well-established anti-inflammatory and antioxidant properties. In this study, we collected fecal samples from mice fed a high-fat diet (HFD) and those on a standard diet (SD), then conducted 16S rRNA sequencing to analyze their gut microbiota. The analysis revealed distinct differences in the dominant bacterial species between the two groups, with a significant decrease in indole-producing probiotics in the HFD mice compared to the SD group. Then we administered oral indole treatment to male C57BL/6J mice with HFD-induced NAFLD and observed a significant improvement in hepatic steatosis and inflammation. Notably, indole alleviated the HFD-induced decline in serum Angiotensin-(1-7) [Ang-(1-7)] levels and Angiotensin-Converting Enzyme 2 (ACE2) expression. To further investigate the role of indole and ACE2 in NAFLD, we conducted experiments using ACE2 knockout (ACE2KO) mice that were also induced with HFD-induced NAFLD and treated with indole. Interestingly, the protective effects of indole were compromised in the absence of ACE2. In HepG2 cells, indole similarly stimulated ACE2 expression and, in an ACE2-dependent manner, reduced ROS generation, maintained mitochondrial membrane potential stability, and increased SIRT3 expression. In summary, our results highlight the formation of a biologically active gut-liver axis between the gut microbiota and the liver through the tryptophan metabolite indole, which mitigates NAFLD in an ACE2-dependent manner. Elevating dietary tryptophan and increasing indole levels may represent an effective approach for preventing and treating NAFLD.

The Relationship between Using Renin-Angiotensin System Inhibitors with Mortality of Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AFib) is a highly prevalent cardiac arrhythmia associated with increased mortality in affected persons. Renin-angiotensin system inhibitors (RASIs) have been suggested as potential therapeutic agents for cardiovascular and renal diseases. OBJECTIVES: However, the relationship between RASIs and mortality in AFib patients remains uncertain. Therefore, the present study was designed and implemented for this purpose. METHODS: We searched PubMed/MEDLINE, Embase, Web of Science (WOS), Cochrane Library, and Scopus databases for studies published until 12 February 2024 with relevant keywords. We included studies that reported mortality outcomes in AFib patients treated with RASIs and non-users. The data extraction and quality assessment processes were conducted, and subgroup analyses and sensitivity analyses were done. The data were analyzed by Stata 15 using statistical tests, such as Chi-square and I2 tests. RESULTS: A total of 15 studies (2007-2024; n=2,178,565 patients) examined the association between RASI drugs and mortality of patients with AFib. The results indicated that compared to the control group, the odds of AFib mortality in the group receiving RASIs were equal to 0.81(95% CI: 0.71-0.92; P-value ≤0.001). The study results did not indicate publication bias (Pvalue= 0.733). During the meta-regression analysis, none of the study variables demonstrated a significant relationship with the observed heterogeneity (P-value > 0.20). Cumulative OR results showed that from 2022 onwards, there was enough evidence to confirm the relationship using RASIs with mortality of patients with AFib. CONCLUSION: Therefore, this meta-analysis suggests that the use of RASI drugs is associated with reduced AFib mortality. However, the authors emphasize the need for further high-quality studies and large-scale randomized clinical trials to validate these findings.

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.

Genetic Polymorphisms of Angiotensin-Converting Enzyme 1 (ACE1) and ACE2 Associated With Severe Acute Respiratory Syndrome COVID-19 in the Palestinian Population.

As a key enzyme of the renin-angiotensin system (RAS), angiotensin-converting enzyme 2 (ACE2) is a validated receptor for SARS-CoV-2, linking RAS to COVID-19. Functional ACE1/ACE2 gene polymorphisms likely cause an imbalance in the ACE1/ACE2 ratio, triggering RAS imbalance and may contribute to COVID-19 complications. This study aimed to investigate four single nucleotide polymorphisms (SNPs) of ACE1 and ACE2 genes, three for ACE1 (rs4343, rs4342, rs4341) and one for ACE2 (rs2285666), in patients with COVID-19 among the Palestinian population. A total of 130 blood samples were collected, including 50 negative controls without COVID-19 infection, 50 cases with COVID-19 infection but not hospitalized, and 30 patients with severe COVID-19 infection hospitalized in the intensive care unit. Fragments of the ACE1 and ACE2 genes, including the targeted SNPs, were amplified using multiplex PCR and subsequently genotyped by next-generation sequencing with specific virtual probes. Our results revealed that ACE2 rs2285666 GG genotype carriers were more prevalent in COVID-19 patients compared to the control group (P=0.049), while no statistical differences were observed in the distribution of ACE1 (rs4343, rs4342, rs4341) variants between COVID-19 patients and the control group. GA carriers of ACE2, rs2285666, among cases and ICU groups were at lower risk of getting COVID-19 infection (P=0.002 and P=0.013, respectively), and they were unlikely to develop fatigue (P=0.043), headache (P=0.007), loss of smell (P=0.028), and dyspnea (P=0.005). Age and comorbidities such as hypertension and coronary artery disease (CAD) were independent risk factors for COVID-19 disease. Symptoms of COVID-19 patients such as fatigue, headaches, runny noses, and loss of smell were significantly higher in non-hospitalized cases of COVID-19, while dyspnea was more frequent in the ICU patients. In conclusion, these findings indicate that the ACE2 rs2285666 GG genotype is associated with an increased risk of COVID-19 infection. This association suggests a potential genetic predisposition linked to the ACE2 gene, which may influence the susceptibility and severity of the disease.

Identification of New Angiotensin-Converting Enzyme Inhibitory Peptides Isolated from the Hydrolysate of the Venom of Nemopilema nomurai Jellyfish.

Recently, jellyfish venom has gained attention as a promising reservoir of pharmacologically active compounds, with potential applications in new drug development. In this investigation, novel peptides, isolated from the hydrolysates of Nemopilema nomurai jellyfish venom (NnV), demonstrate potent inhibitory activities against angiotensin-converting enzyme (ACE). Proteolytic enzymes-specifically, papain and protamex-were utilized for the hydrolysis under optimized enzymatic conditions, determined by assessing the degree of hydrolysis through the ninhydrin test. Comparative analyses revealed that papain treatment exhibited a notably higher degree of NnV hydrolysis compared to protamex treatment. ACE inhibitory activity was quantified using ACE kit-WST, indicating a substantial inhibitory effect of 76.31% for the papain-digested NnV crude hydrolysate, which was validated by captopril as a positive control. The separation of the NnV-hydrolysate using DEAE sepharose weak-anion-exchange chromatography revealed nine peaks under a 0-1 M NaCl stepwise gradient, with peak no. 3 displaying the highest ACE inhibition of 96%. The further purification of peak no. 3 through ODS-C18 column reverse-phase high-performance liquid chromatography resulted in five sub-peaks (3.1, 3.2, 3.3, 3.4, and 3.5), among which 3.2 exhibited the most significant inhibitory activity of 95.74%. The subsequent analysis of the active peak (3.2) using MALDI-TOF/MS identified two peptides with distinct molecular weights of 896.48 and 1227.651. The peptide sequence determined by MS/MS analysis revealed them as IVGRPLANG and IGDEPRHQYL. The docking studies of the two ACE-inhibitory peptides for ACE molecule demonstrated a binding affinity of -51.4 ± 2.5 and -62.3 ± 3.3 using the HADDOCK scoring function.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial.

BACKGROUND: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). PATIENTS AND METHODS: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. RESULTS: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. CONCLUSIONS: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population.

Background: Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population. Methods: The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls). Results: No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10-06). Some of these SNPs were found to be located close to the genes PRKCQ and RIMS1, previously linked with drug-induced angioedema, and also close to the CSMD1 gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs. Conclusions: Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.

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.

Impact of ACEI/ARB use on the survival of hypertensive patients with cancer: A meta­analysis.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive drugs. However, the impact that the use of ACEI and ARB drugs will have on the survival of patients with hypertension and cancer is still unclear. Therefore, the present study aimed to investigate the effects of ACEI and ARB use on the survival of patients with cancer. The Embase, PubMed and Web of Science databases were used to systematically analyze the survival of hypertensive patients with cancer treated with ACEIs or ARBs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the association between ACEI and ARB use and patient survival. The relationship between the survival of patients with certain types of cancer and ACEI and ARB use was evaluated using the calculated HRs. Patients with ovarian, pancreatic, prostate, hepatocellular, lung, esophageal, gastric, colon, nasopharyngeal, head and neck tumors, gallbladder and rectal cancers that used ACEI and ARB analogs had significantly increased survival times, except for patients with breast cancer (HR, 1.04; 95% CI, 0.90-1.19; P<0.01) and uroepithelial carcinoma (HR, 1.15; 95% CI, 0.69-1.94; P<0.01), who had significantly decreased survival times, when compared with patients who did not use these drugs. Analysis of the relationship between the use of ACEIs or ARBs alone or in combination on the overall survival of hypertensive patients with cancer demonstrated that the use of ACEIs alone (HR, 1.00; 95% CI, 0.93-1.08; P<0.01) did not have a significant effect on the survival of these patients. By contrast, the survival time was increased in hypertensive patients with cancer who used either ARBs alone (HR, 0.89; 95% CI, 0.84-0.94; P<0.01) or a combination of ACEIs and ARBs (HR, 0.84; 95% CI, 0.78-0.91; P<0.01). The present meta-analysis demonstrated the potential effects of ACEI and ARB use on the overall survival of patients with cancer. Therefore, investigation of the underlying mechanisms of action of ACEIs and ARBs, as well as the identification of specific groups of patients who may benefit from these interventions, could potentially lead to novel therapeutic options and improve the prognosis of patients with cancer in the future.

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.

A Rare Case of Isolated Extrapulmonary Sarcoidosis With Renal Involvement Sans Pulmonary Findings: Diagnostic Challenges and Clinical Insights.

The cause of sarcoidosis is unknown, and it affects multiple systems with granulomas. Lung lesions are typical, but extrapulmonary findings, especially lymphadenopathy, are present in a significant number of cases. Isolated renal involvement is rare. The presence of noncaseating granulomas on biopsy is a hallmark of sarcoidosis. We present the case of a 59-year-old male with recurrent renal stones who presented with renal failure. The initial diagnosis was challenging due to normal chest imaging and no pulmonary involvement. However, his delayed presentation of calcinosis cutis, an increase in angiotensin-converting enzyme (ACE) level, and the biopsy of the palm lesion with noncaseating granulomas helped us reach the diagnosis. He was started on prednisolone and achieved remission. The report also intends to show that patients with sarcoidosis can present without lung involvement, and physicians should consider sarcoidosis as their differential diagnosis for idiopathic hypercalcemia even if it has no lung or skin findings.

Macrophage Activation Syndrome in Coinciding Pandemics of Obesity and COVID-19: Worse than Bad.

Epigenetic changes have long-lasting impacts, which influence the epigenome and are maintained during cell division. Thus, human genome changes have required a very long timescale to become a major contributor to the current obesity pandemic. Whereas bidirectional effects of coronavirus disease 2019 (COVID-19) and obesity pandemics have given the opportunity to explore, how the viral microribonucleic acids (miRNAs) use the human's transcriptional machinery that regulate gene expression at a posttranscriptional level. Obesity and its related comorbidity, type 2 diabetes (T2D), and new-onset diabetes due to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are additional risk factors, which increase the severity of COVID-19 and its related mortality. The higher mortality rate of these patients is dependent on severe cytokine storm, which is the sum of the additional cytokine production by concomitant comorbidities and own cytokine synthesis of COVID-19. Patients with obesity facilitate the SARS-CoV-2 entry to host cell via increasing the host's cell receptor expression and modifying the host cell proteases. After entering the host cells, the SARS-CoV-2 genome directly functions as a messenger ribonucleic acid (mRNA) and encodes a set of nonstructural proteins via processing by the own proteases, main protease (Mpro), and papain-like protease (PLpro) to initiate viral genome replication and transcription. Following viral invasion, SARS-CoV-2 infection reduces insulin secretion via either inducing ß-cell apoptosis or reducing intensity of angiotensin-converting enzyme 2 (ACE2) receptors and leads to new-onset diabetes. Since both T2D and severity of COVID-19 are associated with the increased serum levels of pro-inflammatory cytokines, high glucose levels in T2D aggravate SARS-CoV-2 infection. Elevated neopterin (NPT) value due to persistent interferon gamma (IFN-γ)-mediated monocyte-macrophage activation is an indicator of hyperactivated pro-inflammatory phenotype M1 macrophages. Thus, NPT could be a reliable biomarker for the simultaneously occurring COVID-19-, obesity- and T2D-induced cytokine storm. While host miRNAs attack viral RNAs, viral miRNAs target host transcripts. Eventually, the expression rate and type of miRNAs also are different in COVID-19 patients with different viral loads. It is concluded that specific miRNA signatures in macrophage activation phase may provide an opportunity to become aware of the severity of COVID-19 in patients with obesity and obesity-related T2D.