Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and cognition impairment in patients with schizophrenia.

RATIONALE: Several lines of evidence indicate that an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) gene may be involved in the pathogenesis of schizophrenia and cognitive impairment. However, the relationship between ACE I/D polymorphism and cognitive impairment in patients with schizophrenia remains unclear. OBJECTIVES: The aim of this study was to examine whether ACE gene I/D polymorphism contributed to cognitive impairment in Chinese patients with schizophrenia, and whether the association between clinical symptoms and cognitive impairment depended on different ACE genotypes. METHODS: The ACE I/D polymorphism was genotyped in 928 schizophrenia patients and 325 healthy controls using a case-control design. The severity of psychopathological symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functioning was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: There were significant differences in genotype and allele frequencies of the ACE I/D polymorphism between patients and healthy controls (both P < 0.01). After controlling for demographic characteristics, patients who are homozygous carriers of D and I performed worse on the RBANS attention index than heterozygous carriers (P = 0.009). In addition, attention index score was negatively correlated with PANSS negative symptom score in patients of all genotypes (all P < 0.05), and positively correlated with positive symptom score only in the I/I genotype (P = 0.005). CONCLUSIONS: These findings suggest that ACE I/D gene variants play a role in susceptibility to schizophrenia, specific cognitive impairment and the association between clinical symptoms and cognitive impairment in schizophrenia patients.

Integrated analysis of gut microbiome and its metabolites in ACE2-knockout and ACE2-overexpressed mice.

Background: Aberrant activation of the classic renin-angiotensin system (RAS) and intestinal micro dysbiosis adversely affect insulin resistance (IR), dyslipidemia, and other metabolic syndrome markers. However, the action of angiotensin-converting enzyme 2 (ACE2) and gut health in systemic homeostasis vary, and their interaction is not completely understood. Methods: We adopted a combinatory approach of metabolomics and fecal 16S rRNA analysis to investigate gut microbiota and metabolite in two different mouse models, ACE2 knockout (ACE2 KO) mice and the ACE2-overexpressing obese mice. Results: 16S rRNA gene sequencing revealed that ACE2 influences microbial community composition and function, and ACE2 KO mice had increased Deferribacteres, Alcaligenaceae, Parasutterella, Catenibacterium, and Anaerotruncus, with decreased short-chain fatty acid (SCFA)-producing bacteria (Marvinbryantia and Alistipes). In contrast, ACE2-overexpressed mice exhibited increased anti-inflammatory probiotic (Oscillospiraceae, Marinifilaceae, and Bifidobacteriaceae) and SCFA-producing microbes (Rikenellaceae, Muribaculaceae, Ruminococcaceae, Odoribacter, and Alistipes) and decreased Firmicutes/Bacteroidetes, Lactobacillaceae, Erysipelotrichaceae, and Lachnospiraceae. Metabolome analysis indicated differential metabolites in ACE2 KO and ACE2-overexpression mice, especially the glucolipid metabolism-related compounds. Furthermore, correlation analysis between gut microbiota and metabolites showed a dynamic mutual influence affecting host health. Conclusion: Our study confirms for the first time a significant association between ACE2 status and gut microbiome and metabolome profiles, providing a novel mechanism for the positive effect of ACE2 on energy homeostasis.

Angiotensin receptor blockers versus angiotensin converting enzyme inhibitors in acute myocardial infarction without heart failure.

BACKGROUND: Whether angiotensin II receptor blocker (ARB) can be an alternative to angiotensin-converting enzyme inhibitor (ACEI) in patients without heart failure (HF) after acute myocardial infarction (MI) remains controversial. The aim of this study was to compare clinical outcomes between initial ARB and ACEI therapy in patients with MI without HF. METHODS: Between 2010 and 2016, a total of 31,013 patients who underwent coronary revascularization for MI with prescription of ARB or ACEI at hospital discharge were enrolled from the Korean nationwide medical insurance data. Patients who had HF at index MI were excluded. The primary outcome was all-cause death. The secondary outcomes included recurrent MI, hospitalization for new heart HF, stoke, and a composite of each outcome. RESULTS: Of 31,013 patients, ARBs were prescribed in 12,685 (40.9%) and ACEIs in 18,328 (59.1%). Patients receiving ARB had a lower discontinuation rate compared with those receiving ACEI (28.2% versus 43.5%, adjusted hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.31-0.37, p<0.01). During a median follow-up of 2.2 years, 2,480 patients died. The incidence rate of all-cause death in patients receiving ARB and those receiving ACEI was 27.7 and 22.9 per 1,000 person-years, respectively (adjusted HR 1.04; 95% CI, 0.95-1.13; p=0.40). There were no significant differences in the secondary outcomes between patients receiving ARB and those receiving ACEI, except stroke (19.2 vs. 13.6 per 1,000 person-years; adjusted HR 1.17; 95% CI 1.04-1.32; p=0.01). In a subgroup analysis, a higher mortality was observed with ARBs compared to ACEIs in patients with diabetes. CONCLUSIONS: In this nationwide cohort, there was no significant difference in the incidence of all-cause death between ARB and ACEI as discharge medications in patients with MI without HF. ARBs would be an alternative to ACEIs for those intolerant to ACEI therapy.

Real-world experience of angiotensin receptor-neprilysin inhibitors in patients with heart failure and dialysis.

Introduction: Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation. Methods: This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness. Results: Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28-3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings. Conclusion: ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

A Comparative Analysis of SARS-CoV-2 Variants of Concern (VOC) Spike Proteins Interacting with hACE2 Enzyme.

In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) simulation is utilized to compare the behaviors of SARS-CoV-2 and its Variants of Concern (VOC)-Alpha, Beta, Gamma, Delta, and Omicron-with the hACE2 protein. Protein structures from the Protein Data Bank (PDB) were aligned and trimmed for consistency using Chimera, focusing on the receptor-binding domain (RBD) responsible for ACE2 interaction. MD simulations were performed using Visual Molecular Dynamics (VMD) and Nanoscale Molecular Dynamics (NAMD2), and salt bridges and hydrogen bond data were extracted from the results of these simulations. The data extracted from the last 5 ns of the 10 ns simulations were visualized, providing insights into the comparative stability of each variant's interaction with ACE2. Moreover, electrostatics and hydrophobic protein surfaces were calculated, visualized, and analyzed. Our comprehensive computational results are helpful for drug discovery and future vaccine designs as they provide information regarding the vital amino acids in protein-protein interactions (PPIs). Our analysis reveals that the Original and Omicron variants are the two most structurally similar proteins. The Gamma variant forms the strongest interaction with hACE2 through hydrogen bonds, while Alpha and Delta form the most stable salt bridges; the Omicron is dominated by positive potential in the binding site, which makes it easy to attract the hACE2 receptor; meanwhile, the Original, Beta, Delta, and Omicron variants show varying levels of interaction stability through both hydrogen bonds and salt bridges, indicating that targeted therapeutic agents can disrupt these critical interactions to prevent SARS-CoV-2 infection.

Effects of Cardioprotective Drugs on 90-Day Mortality or Heart Transplantation in Patients With Fulminant Myocarditis.

Background: Cardioprotective drugs have not been previously shown to improve the prognosis in patients with fulminant myocarditis presentation (FMP). We aimed to investigate whether cardioprotective drugs, including angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and ß-blocker, administered during hospitalization improved the prognosis in patients with FMP. Methods and Results: This multicenter cohort study conducted in Japan included 755 patients with clinically diagnosed FMP. Those who died within 14 days of admission were excluded, and 588 patients (median age 53 [37-65] years and 40% female) were evaluated. The primary outcome was the composite of 90-day mortality or heart transplantation. The patients were divided into 4 groups according to whether they were administered ACEI/ARB or ß-blocker during hospitalization. Administration of ACEI/ARB without ß-blocker improved the overall patient outcomes (log-rank test [vs. ACEI/ARB - and ß-blocker -]: ACEI/ARB + and ß-blocker -, P<0.001; ACEI/ARB - and ß-blocker +, P=0.256). Subsequently, a matched cohort of 146 patient pairs was generated for patients with or without ACEI/ARB administration during hospitalization. The outcome-free survival at 90 days was significantly higher in the ACEI/ARB administration group than in the non-administration group (hazard ratio 0.37; 95% confidence interval 0.19-0.71). Conclusions: Administration of ACEI or ARB during hospitalization was associated with favorable outcomes in terms of 90-day mortality and heart transplantation events in patients with clinically diagnosed FMP.

Exploring the Molecular Underpinnings of Skin Regeneration and Wound Healing: The Role of Renin Angiotensin.

The aim of this study is to review the role of renin-angiotensin in skin regeneration and wound healing with a focus on molecular mechanisms. Angiotensin receptor type 1 (AT1R) are abundant in the wounded area, and thus, lead to the activation of ERK, STAT1, and STAT3 which can lead to epidermal self-renewal. The expression of Renin Angiotensin System (RAS) components was significantly lower in wounds caused by burning, rather than intact skin, noting that RAS is involved in the re-epithelialization of skin. ERK, STAT and STAT3 are the targets of Ang II, indicating that RAS active components are involved in fibroblast, stem cells and keratinocyte migration. The effect of inhibiting the RAS on wound healing is context-dependent. On one hand, it is suggested that inhibiting RAS during this phase may slow down wound healing speed. On the other hand, studies have shown that RAS inhibition in this phase can lead to α-SMA activation, ultimately accelerating the wound healing process. Most of the investigations indicate that the inhibition of RAS with Angiotensin Receptor Blockers (ARBs) and Angiotensin Converting Enzyme (ACE) plays a significant role in tissue remodeling in the last phase of wound healing. It has been shown that the inhibition of RAS can inhibit scar formation and fibrosis through the downregulation of inflammatory and fibrogenic agents, such as TGF-ß, SMAD2/3, and TAK1, PDGF-BB, and HSP47. To sum up, that local administration of RAS regulators might lead to less scar formation and inflammation in the last phase of wound closure.

Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial.

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

Engineering a NanoBiT biosensor for detecting angiotensin-converting enzyme-2 (hACE2) interaction with SARS-CoV-2 spike protein and screening the inhibitors to block hACE2 and spike interaction.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is facilitated by its trimeric surface spike protein, which binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. This critical interaction facilitates viral entry and is a primary target for therapeutic intervention against COVID-19. However, it is difficult to fully optimize viral infection using existing protein-protein interaction methods. Herein, we introduce a nano-luciferase binary technology (NanoBiT)-based pseudoviral sensor designed to stimulate the dynamics of viral infection in both living cells and animals. Infection progression can be dynamically visualized via a rapid increase in luminescence within 3 h using an in vivo imaging system (IVIS). Inhibition of viral infection by baicalein and baicalin was evaluated using a NanoBiT-based pseudoviral sensor. These results indicate that the inhibitory efficacy of baicalein was strengthened by targeting the spike protein, whereas baicalin targeted the hACE2 protein. Additionally, under optimized conditions, baicalein and baicalin provided a synergistic combination to inhibit pseudoviral infection. Live bioluminescence imaging was used to evaluate the in vivo effects of baicalein and baicalin treatment on LgBiT-hACE2 mice infected with the BA.2-SmBiT spike pseudovirus. This innovative bioluminescent system functions as a sensitive and early-stage quantitative viral transduction in vitro and in vivo. This platform provides novel opportunities for studying the molecular biology of animal models.

Fermentation of Rice, Oat, and Wheat Flour by Pure Cultures of Common Starter Lactic Acid Bacteria: Growth Dynamics, Sensory Evaluation, and Functional Properties.

Recent consumer demand for non-dairy alternatives has forced many manufacturers to turn their attention to cereal-based non-alcoholic fermented products. In contrast to fermented dairy products, there is no defined and standardized starter culture for manufacturing cereal-based products. Since spontaneous fermentation is rarely suitable for large-scale commercial production, it is not surprising that manufacturers have started to adopt centuries-known dairy starters based on lactic acid bacteria (LABs) for the fermentation of cereals. However, little is known about the fermentation processes of cereals with these starters. In this study, we combined various analytical tools in order to understand how the most common starter cultures of LABs affect the most common types of cereals during fermentation. Specifically, 3% suspensions of rice, oat, and wheat flour were fermented by the pure cultures of 16 LAB strains belonging to five LAB species-Lacticaseibacillus paracasei, Lactobacillus delbrueckii, Lactobacillus helveticus, Streptococcus thermophilus, and Lactococcus lactis. The fermentation process was described in terms of culture growth and changes in the pH, reducing sugars, starch, free proteins, and free phenolic compounds. The organoleptic and rheological features of the obtained fermented products were characterized, and their functional properties, such as their antioxidant capacity and angiotensin-converting enzyme inhibitory activity, were determined.

Clinical Significance and Patterns of Potential Drug-Drug Interactions in Cardiovascular Patients: Focus on Low-Dose Aspirin and Angiotensin-Converting Enzyme Inhibitors.

Objective: This study assessed the patterns and clinical significance of potential drug-drug interactions (pDDIs) in patients with diseases of the cardiovascular system. Methods: Electronic health records (EHRs), established in 2018-2023, were selected using the probability serial nested sampling method (n = 1030). Patients were aged 27 to 95 years (65.0% men). Primary diagnosis of COVID-19 was present in 17 EHRs (1.7%). Medscape Drug Interaction Checker was used to characterize pDDIs. The Mann-Whitney U test and chi-square test were used for statistical analysis. Results: Drug numbers per record ranged from 1 to 23 in T-List and from 1 to 20 in P-List. In T-List, 567 drug combinations resulted in 3781 pDDIs. In P-List, 584 drug combinations resulted in 5185 pDDIs. Polypharmacy was detected in 39.0% of records in T-List versus 65.9% in P-List (p-value < 0.05). The rates of serious and monitor-closely pDDIs due to 'aspirin + captopril' combinations were significantly higher in P-List than in T-List (p-value < 0.05). The rates of serious pDDIs due to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations were significantly lower in P-List compared with the corresponding rates in T-List (p-value < 0.05). Serious pDDIs due to administration of aspirin with fosinopril, perindopril, and ramipril were detected less frequently in T-List (p-value < 0.05). Conclusions: Obtained data may suggest better patient adherence to 'aspirin + enalapril' and 'aspirin + lisinopril' combinations, which are potentially superior to the combinations of aspirin with fosinopril, perindopril, and ramipril. An abundance of high-order pDDIs in real-world clinical practice warrants the development of a decision support system aimed at reducing pharmacotherapy-associated risks while integrating patient pharmacokinetic, pharmacodynamic, and pharmacogenetic information.

Epigenetic Regulation of the Renin-Angiotensin-Aldosterone System in Hypertension.

Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.

Hyponatremia in geriatric patients.

Hyponatremia is the most frequent electrolyte imbalance in geriatric medicine. Causes of hyponatremia were retrospectively analyzed in all in-patients treated in 2016 (N = 2267, 1564 women, 703 men, mean age ± standard deviation 81.9 ± 7.6 years). Any form of hyponatremia on admission, during the stay or on discharge was noted in 308 patients (13.6%, 231 women, 77 men; mean age ± standard deviation 83.1 ± 7.3 years, p = 0.009 vs. age of all patients). Women had a higher probability of developing hyponatremia compared to men (p = 0.019), 131 patients were hypovolemic, and dyspnea as an indicator of hypervolemia was noted in 71 patients.Only 12 patients suffering from hyponatremia (3.9%) did not receive any of the potentially sodium-lowering drugs assessed (diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, antidepressants, neuroleptics, nonsteroidal antirheumatics, carbamazepine, oxcarbazepine). The median number of drugs per patient potentially lowering the plasma sodium level was 3 and the maximum number was 7.Hypovolemic hyponatremia and the syndrome of inadequate antidiuretic hormone secretion were the most important causes of hyponatremia. Adverse drug effects were the main origins of both conditions. In patients with hyponatremia the drug load influencing plasma sodium level should be minimized, thiazide diuretics should be avoided and older individuals should receive a diet with sufficient salt content.

Presence of Modified Peptides with High Bioavailability and Angiotensin-Converting Enzyme Inhibitory Activity in Japanese Fermented Soybean Paste (Miso).

Not only free amino acids and normal short-chain peptides but also modified amino acids, such as N-acetyl- and N-formyl amino acids, monoamines, polyamines, and modified peptides, such as isomerized aspartyl peptides, pyroglutamyl peptides, and diketopiperazines, were identified in Japanese fermented soy paste (miso) prepared using different fungal starters, rice, barley, and soybean-koji. One hour after oral administration of water extract of soybean-koji miso to rats, the modified peptides increased significantly in the lumen upon the ingestion, while the normal peptides did not. In the blood from the portal vein and abdominal vena cava, 17 and 15 diketopiperazines, 16 and 12 isomerized aspartyl peptides, and 2 and 1 pyroglutamyl peptides significantly increased to approximately 10-400 nM, respectively. The modified peptides, which increased in rat blood, showed angiotensin-converting enzyme (ACE) inhibitory activity in a dose-dependent manner, indicating multiple ACE inhibitory peptides with high bioavailability in miso. Among them, l-ß-Asp-Pro showed the highest ACE inhibitory activity (IC50 4.8 µM).

Effects of anaerobic treatment on the non-volatile components and angiotensin-converting enzyme (ACE) inhibitory activity of purple-colored leaf tea.

This study investigated the effect of anaerobic treatment on the non-volatile components and angiotensin-converting enzyme (ACE) inhibitory activity in purple-colored leaf tea. Results showed that after 8 h of anaerobic treatment, the γ-aminobutyric acid (GABA) content significantly increased from 0.02 mg/g to 1.72 mg/g (p < 0.05), while lactic acid content gradually rose from non-detectable levels to 3.56 mg/g. Notably, certain flavonols like quercetin and myricetin exhibited significant increments, whereas the total anthocyanins (1.01 mg/g) and epigallocatechin-3-(3''-O-methyl) gallate (13.47 mg/g) contents remained almost unchanged. Furthermore, the ACE inhibition rate of purple-colored leaf tea increased significantly from 42.16% to 49.20% (p < 0.05) at a concentration of 2 mg/mL. Moreover, galloylated catechins showed stronger ACE inhibitory activity than non-galloylated catechins in both in vitro ACE inhibitory activity and molecular docking analysis. These findings might contribute to the development of special purple-colored leaf tea products with potential therapy for hypertension.

Histopathological impact of SARS-CoV-2 on the liver: Cellular damage and long-term complications.

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

In vitro inhibitor effect and molecular docking of thiamine (vitamin B1), riboflavin (vitamin B2), and reference inhibitor captopril on angiotensin-converting enzyme purified from sheep plasma.

OBJECTIVE: Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a very important factor in the regulation of blood pressure. Also, the inhibition of ACE with natural compounds has been a very important research area in the treatment of high blood pressure. ACE was purified and characterized from sheep plasma. Molecular docking studies and the inhibition effect of thiamine, riboflavin, and captopril on ACE were investigated. METHODS: Herein, ACE was purified from sheep plasma by affinity chromatography. The effect of thiamine and riboflavin on ACE was researched. Molecular docking studies were performed to understand the molecular interactions between thiamine, riboflavin, and captopril with ACE. RESULTS: The purification coefficient was found to be 8636 fold. The binding energy of thiamine, riboflavin, and captopril was found to be -6.7 kcal/mol, -8.1 kcal/mol, and -5.5 kcal/mol, respectively. Thiamine conformed to three conventional hydrogen bonds with ASP:415, HIS:513, and LYS:454. Riboflavin formed four conventional hydrogen bonds with GLN:281, GLU:376, THR:282, and TYR:520. Captopril formed two conventional hydrogen bonds with ARG:124, one conventional hydrogen bond with TYR:62 and ASN:85, and one carbon-hydrogen bond with ASN:66. Molecular docking results showed that thiamine, riboflavin, and captopril interacted with ACE through hydrogen bonding and hydrophobic interactions. Thiamine and riboflavin indicated significant inhibition effects on ACE. The IC50 values of thiamine, riboflavin, and captopril were found as 960.56 µM, 11.02 µM, and 1.60 nM, respectively. Ki values for thiamine, riboflavin, and captopril were determined as 1352.04 µM, 12.30 µM, and 1.06 nM, respectively. CONCLUSION: In this work, it was concluded that thiamine and riboflavin may have preventive and therapeutical impacts against high blood pressure with their ACE inhibitor effect. Thiamine and riboflavin showed a lower inhibitory effect with a higher IC50 than captopril. However, when the inhibitory effect of thiamine and riboflavin vitamins is compared to captopril, it is concluded that they may be natural inhibitors with fewer side effects.

A Case of Diffuse Scleroderma Presenting as Hypertensive Encephalopathy Due to Scleroderma Renal Crisis.

This case report details a rare presentation of diffuse scleroderma, where a 38-year-old female developed hypertensive encephalopathy due to scleroderma renal crisis (SRC). SRC, characterized by sudden severe hypertension and renal failure, poses a life-threatening emergency. The patient's clinical features, including skin changes and abnormalities on nailfold capillaroscopy, facilitated the diagnosis of diffuse scleroderma. Comprehensive diagnostic investigations revealed multisystem involvement. Management involved angiotensin-converting enzyme inhibitors, hydroxychloroquine, and packed red cell transfusions, highlighting a holistic therapeutic approach. This case underscores the importance of recognizing diverse scleroderma manifestations in hypertensive emergencies for timely intervention and improved outcomes.

In Silico Screening of Bioactive Peptides in Stout Beer and Analysis of ACE Inhibitory Activity.

Stout beer was selected as the research object to screen angiotensin-converting enzyme (ACE) inhibitory peptides. The peptide sequences of stout beer were identified using ultra-performance liquid chromatography-quadrupole-Orbitrap mass spectrometry with de novo, and 41 peptides were identified with high confidence. Peptide Ranker was used to score the biological activity and six peptides with a score ≥ 0.5 were screened to predict their potential ACE inhibitory (ACEI) activity. The toxicity, hydrophilicity, absorption, and excretion of these peptides were predicted. In addition, molecular docking between the peptides and ACE revealed a significant property of the peptide DLGGFFGFQR. Furthermore, molecular docking conformation and molecular dynamics simulation revealed that DLGGFFGFQR could be tightly bound to ACE through hydrogen bonding and hydrophobic interaction. Lastly, the ACEI activity of DLGGFFGFQR was confirmed using in vitro evaluation and the IC50 value was determined to be 24.45 µM.

Ile-Pro-Pro attenuates sympathetic activity and hypertension.

Isoleucine-proline-proline (Ile-Pro-Pro, IPP) is a natural food source tripeptide that inhibits angiotensin-converting enzyme (ACE) activity. The aim of this study was to determine the central and peripheral roles of IPP in attenuating sympathetic activity, oxidative stress and hypertension. Male Sprague-Dawley rats were subjected to sham-operated surgery (Sham) or two-kidney one-clip (2K1C) surgery to induce renovascular hypertension. Renal sympathetic nerve activity and blood pressure were recorded. Bilateral microinjections of IPP to hypothalamic paraventricular nucleus (PVN) attenuated sympathetic activity (-16.1 ± 2.5%, P < 0.001) and hypertension (-8.7 ± 1.5 mmHg, P < 0.01) in 2K1C rats by inhibiting ACE activity and subsequent angiotensin II and superoxide production in the PVN. Intravenous injections of IPP also attenuated sympathetic activity (-15.1 ± 2.1%, P < 0.001) and hypertension (-16.8 ± 2.3 mmHg, P < 0.001) via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. The duration of the effects of the intravenous IPP was longer than those of the PVN microinjection, but the sympatho-inhibitory effect of intravenous injections occurred later than that of the PVN microinjection. Intraperitoneal injection of IPP (400 pmol/day for 20 days) attenuated hypertension and vascular remodeling via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. These results indicate that IPP attenuates hypertension and sympathetic activity by inhibiting ACE activity and oxidative stress. The sympathoinhibitory effect of peripheral IPP is mainly caused by the ACE inhibition in PVN, and the antihypertensive effect is related to the sympathoinhibition and the arterial ACE inhibition. Long-term intraperitoneal IPP therapy attenuates hypertension, oxidative stress and vascular remodeling.