Angiotensin-converting Enzyme Levels Research Articles

Dandelion root extracts and taraxasterol inhibit LPS‑induced colorectal cancer cell viability by blocking TLR4‑NFκB‑driven ACE2 and TMPRSS2 pathways.

Colorectal cancer is the fourth leading cause of cancer-related death worldwide. Notably, abnormalities in intestinal bacteria may contribute to the initiation or progression of colorectal cancer. Lipopolysaccharide (LPS), a bacterial endotoxin, is elevated in patients with colorectal cancer. The present study investigated the protective effects of dandelion root extracts and taraxasterol (TS; a major pharmacologically active compound in dandelion root extracts) on LPS-induced colorectal cancer cell viability, as well as the underlying mechanisms. Cell viability was assessed by MTT assay, and protein and gene expression levels were determined by western blotting and quantitative PCR. It was revealed that LPS at a low dose (0.5 µg/ml) significantly promoted the viability of human colorectal cancer cells but did not affect normal colon epithelial cells. The addition of dandelion root extracts (0.1-1 mg/ml) or TS (0.05-1 µg/ml) was able to reverse the LPS-induced increase in colorectal cancer cell viability and colony formation. Mechanistically, dandelion root extracts or TS may inhibit the LPS-promoted toll-like receptor 4 (TLR4)/NFκB-p65 pathway and transcription levels of pro-inflammatory genes (TNFα, IL4 and IL6). Compared with normal colon epithelial cells, human colorectal cancer cells had higher expression levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which could be further enhanced by LPS treatment but this was reversed by co-incubation with dandelion root extracts or TS. In addition, suppression of the TLR4/NFκB-p65 pathway with CLI095 significantly reversed the stimulatory effect of LPS on the expression levels of ACE2 and TMPRSS2, whereas TNFα (10 ng/ml) markedly induced the expression levels of ACE2 and TMPRSS2. In conclusion, the present study suggested that dandelion root extracts and TS could be used as prevention strategies for reversing bacteria-driven colorectal cancer cell viability.

#68 Novel clinical application of urinary angiotensin-converting enzyme assay in renal sarcoidosis: a retrospective observational study

Abstract Background and Aims Renal manifestations of sarcoidosis are observed in approximately 1–5% and characterized mainly by granulomatous interstitial nephritis, which could lead to kidney failure. Angiotensin-converting enzyme (ACE) reflects the presence of granuloma; hence, serum ACE and tubular injury markers are measured in renal sarcoidosis (RS); however, they either have low sensitivity or low specificity. Although its practicality has not been established, the use of ACE levels in cerebrospinal fluid has been reported for neuro-sarcoidosis. Therefore, we hypothesized that urinary ACE could reflect granuloma presence in the kidneys and could be a disease-specific marker for RS. Method This was a single-center, retrospective observational study. We evaluated clinical characteristics and kidney biopsy findings from electronic medical record surveys and kidney biopsy specimens. The control groups included sarcoidosis without renal involvement (SAR-control) and tubulointerstitial nephritis without a sarcoidosis etiology (TIN-control). Serum and urinary ACE levels were measured, and urinary fractional excretion of ACE (FEACE) was investigated. Serum ACE assay and urinary ACE levels were measured using the colorimetric method with p-hydroxybenzoyl-glycyl-L-histidyl-L-leucine. A total of six patients (three with RS; one with sarcoidosis as controls; and two with TIN controls) with undetectable urinary ACE levels were excluded from the urinary ACE and FEACE analyses. Tubulointerstitial lesions were visually assessed for essentially normal (%), inflammatory cell infiltrates (%), tubular atrophy (%), and interstitial fibrosis (%) by several board-certified nephrologists, and analyzed the correlation of these lesions with each marker. Results This study included 18 patients with RS, 18 as SAR-control, and 10 as TIN-control. Serum ACE, urinary ACE, and FEACE levels in the RS group were significantly higher than those in the control groups. Receiver operating characteristic analysis identified FEACE and serum ACE levels as useful biomarkers for diagnosing RS among patients with both controls, respectively. In the RS group, FEACE was positively correlated with the degree of tubulointerstitial injury (r = 0.69, P = 0.0045), and the cutoff value of FEACE for diffuse tubulointerstitial injury (50.0% or more) was 0.39%, with a sensitivity and specificity of 100.0%. Furthermore, obvious positive correlations were observed among FEACE, inflammatory cell infiltrates (r = 0.53, P = 0.044), and interstitial fibrosis (r = 0.56, P = 0.029) in the RS group but not in the TIN-control. Conclusion Combination with serum and urinary ACE could help diagnose and assess disease severity among patients with RS.

Neurosarcoidosis-Induced Winging Scapula: Efficacy of Infliximab Treatment in Addressing Multifaceted Challenges.

Sarcoidosis, a systemic granulomatous disease primarily affecting the respiratory and lymphatic systems, can rarely manifest as neurosarcoidosis either in isolation or alongside other systemic symptoms. Here, we describe the case of a 45-year-old male with a history of recurrent sinusitis refractory to antibiotics, who presented to the emergency department with sinus congestion and dysphagia. Clinical examination revealed left lower motor neuron facial palsy and enlarged submandibular salivary glands. Despite obtaining negative results from various antibody panels, the patient exhibited elevated Angiotensin Converting Enzyme levels of 83 nmol/kg/min. Additionally, computed tomography chest scans revealed bilateral hilar and mediastinal lymph node enlargement, findings consistent with sarcoidosis. Otorhinolaryngology evaluation for dysphagia confirmed left vocal cord palsy. Following a negative infectious disease workup, submandibular salivary gland biopsy confirmed sarcoidosis. Treatment with mycophenolate mofetil and oral steroids led to gradual improvement in salivary gland swelling, dysphagia, and facial palsy. However, worsening left shoulder pain prompted further investigation, revealing winging of the left scapula on repeat examination. Magnetic resonance imaging (MRI) of the cervical spine revealed a six mm hyperintensity in the left dorsal cord at the C5 level, suggesting possible neurosarcoidosis vs. demyelinating disease. Subsequently, the patient was prescribed anti-tumor necrosis factor alpha inhibitor infliximab. Subsequent MRI of the cervical spine, conducted six months after initiating Infliximab therapy, indicated resolution of the lesions. This positive outcome was supported by the patient's report of symptom improvement, notably reduced shoulder pain and improvement in left scapular winging. This case underscores the unusual co-occurrence of Bell's palsy and vocal cord palsy in the same patient, along with the potential contribution of neurosarcoidosis to the winged scapula. Additionally, it sheds light on the positive response of neurosarcoidosis to Infliximab therapy.

Pyridostigmine attenuates hypertension by inhibiting activation of the renin-angiotensin system in the hypothalamic paraventricular nucleus.

Activation of the renin-angiotensin system (RAS) triggers oxidative stress and an inflammatory response in the hypothalamic paraventricular nucleus (PVN), in turn increasing the sympathetic hyperactivity that is a major cause of hypertension. Pyridostigmine has cardioprotective effects by suppressing the RAS of myocardial tissue. However, whether pyridostigmine attenuates hypertension by inhibiting the RAS of the PVN remains unclear. We thus investigated the effect and mechanism of pyridostigmine on two-kidney one-clip (2K1C)-induced hypertension. 2K1C rats received pyridostigmine, or not, for 8weeks. Cardiovascular function, hemodynamic parameters, and autonomic activity were measured. The PVN levels of pro-/anti-inflammatory cytokines, oxidative stress, and RAS signaling molecules were evaluated. Our results showed that hypertension was accompanied by cardiovascular dysfunction and an autonomic imbalance characterized by enhanced sympathetic but diminished vagal activity. The PVN levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), NOX-2, and malondialdehyde (MDA) increased; those of IL-10 and superoxide dismutase (SOD) decreased. Moreover, the RAS signaling pathway was activated, as evidenced by increased levels of the angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the Ang II type 1 receptor (AT1R) and a decreased AT2R level. Pyridostigmine lowered blood pressure and improved cardiovascular function, associated with restoration of the autonomic balance. Meanwhile, pyridostigmine decreased PVN IL-6, TNF-α, ROS, NOX-2, and MDA levels and increased IL-10 and SOD levels. Additionally, pyridostigmine suppressed PVN ACE, Ang II, and AT1R levels and increased AT2R expression. Pyridostigmine attenuated hypertension by inhibiting PVN oxidative stress and inflammation induced by the RAS.

Serum AXL is a potential molecular marker for predicting COVID-19 progression.

The severity, symptoms, and outcome of COVID-19 is thought to be closely linked to how the virus enters host cells. This process involves the key roles of angiotensin-converting enzyme 2 (ACE2) and the Tyrosine protein kinase receptor UFO (AXL) receptors. However, there is limited research on the circulating levels of ACE2 and AXL and their implications in COVID-19. A control group of 71 uninfected individuals was also included in the study. According to the Guidance for Corona Virus Disease 2019 (10th edition), a cohort of 358 COVID-19 patients were categorized into non-severe and severe cases. Serum ACE2/AXL levels in COVID-19 patients were detected by enzyme-linked immunosorbent assay (ELISA) at different time points post-COVID-19 infection, including days 0-7, 8-15, 31-179 and >180 days. Serum SARS-CoV-2 IgG/IgM antibodies in COVID-19 patients at the same intervals were assessed by using an iFlash 3000 Chemiluminescence Immunoassay Analyzer. The receiver operating characteristic (ROC) curves were used to assess the diagnostic value of the biological markers, and the association between laboratory parameters and illness progression were explored. Compared with the uninfected group, the levels of ACE2 and AXL in the COVID-19 group were decreased, and the SARS-COV-2 IgG level was increased. AXL (AUC = 0.774) demonstrated a stronger predictive ability for COVID-19 than ACE2. In the first week after infection, only the level of AXL was statistically different between severe group and non-severe group. After first week, the levels of ACE2 and AXL were different in two groups. Moreover, in severe COVID-19 cases, the serum ACE2, AXL, and SARS-COV-2 IgM levels reached a peak during days 8-15 before declining, whereas serum SARS-COV-2 IgG levels continued to rise, reaching a peak at day 31-180 days before decreasing. In addition, the AXL level continued to decrease and the SARS-COV-2 IgG level continued to increase in the infected group after 180 days compared to the uninfected group. The levels of serum ACE2 and AXL correlate with COVID-19 severity. However, AXL can also provide early warning of clinical deterioration in the first week after infection. AXL appears to be a superior potential molecular marker for predicting COVID-19 progression.

التنبؤ المبكر بالاعتلال الكلوي لمرضى عراقين مصابين بالسكري النوع الثاني بدلالة تقييم بعض العوامل البيوكيمائية ذات الصلة

داء السكري من النوع 2 (T2DM) هو مرض معقد يصيب العديد من الأعضاء إلى جانب البنكرياس مثل الكلى والكبد والدماغ والعين. بسبب ارتفاع السكر في الدم لفترات طويلة وعدم السيطرة على مرض السكري مع وجود عوامل خطر أخرى ، يمكن أن تحدث مضاعفات مرض السكري. تشمل مضاعفات مرض السكري مضاعفات الأوعية الدموية الدقيقة والأوعية الدموية الكبيرة التي تستهدف الكلى. تهدف الدراسة الحالية إلى التحقق من مستوى الانجوتينسن المحول للانزيم ACE-2)) ، عامل نمو النسيج الضام (CTGF) جنبًا إلى جنب مع بعض العوامل البيوكيميائية ذات الصلة في النساء المصابات بداء السكري واعتلال الكلية السكري مقارنة بالضوابط الصحية. اشتملت الدراسة على 90 مريض تتراوح أعمارهم بين 30-65 سنة. يعانون من مرض السكري من النوع 2 مقسمون إلى ثلاث مجاميع على أساس معايير ACR تشمل البيلة الألبومينية الطبيعية ، البيلة الألبومينية الدقيقة ، البيلة الألبومينية الكبيرة 30 مريضًا لكل مجموعة و 30 شخصًا يتمتعون بصحة جيدة كانوا بمثابة المجموعة الضابطة ، منمن زاروا مستشفى بغداد التعليمي / المدينة الطبية و مستشفى اليرموك التعليمي ، في الفترة ما بين ديسمبر 2021 ومايو 2022. تم تحديد مستوياتACE-2 و CTGF باستخدام تقنية ELISA. أظهرت النتائج وجود فروق ذات دلالة إحصائية بين مجموعات المرضى والمجموعة الضابطة لعامل CTGF ، ووجد أن مستويات ACE-2 تزيد بشكل كبير في مجموعات المرضى عن مجموعة التحكم الصحية. كما أظهرت النتائج أن كلا من سكر الدم الصائم FBS و هيموكلوبينA1C (HbA1C)قد زاد بشكل ملحوظ في مجموعات المرضى مقارنة بالمجموعة الصحية. علاوة على ذلك ، كشفت قيم معدل الترشيح الكبيبي المقدر( ( eGFR عن فروق ذات دلالة إحصائية بين جميع المجموعات المدروسة ، وكذلك اظهرت نتائج ACR وجود فروقات ذات دلالة إحصائية بين مجموعات المرضى الثلاثة ، والتي تمثل المعايير الأساسية لتصنيف مجموعات المرضى. على أساس النتائج التي تم الحصول عليها في هذه الدراسة ، يمكن استنتاج ان عاملي ACE-2 و CTGF يمكن تطبيقهما كواسمات تنبؤية مبكرة موثوقة للكشف عن المرض.

Cell type-specific adaptation of the SARS-CoV-2 spike.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can infect various human tissues and cell types, principally via interaction with its cognate receptor angiotensin-converting enzyme-2 (ACE2). However, how the virus evolves in different cellular environments is poorly understood. Here, we used experimental evolution to study the adaptation of the SARS-CoV-2 spike to four human cell lines expressing different levels of key entry factors. After twenty passages of a spike-expressing recombinant vesicular stomatitis virus (VSV), cell-type-specific phenotypic changes were observed and sequencing allowed the identification of sixteen adaptive spike mutations. We used VSV pseudotyping to measure the entry efficiency, ACE2 affinity, spike processing, TMPRSS2 usage, and entry pathway usage of all the mutants, alone or in combination. The fusogenicity of the mutant spikes was assessed with a cell-cell fusion assay. Finally, mutant recombinant VSVs were used to measure the fitness advantage associated with selected mutations. We found that the effects of these mutations varied across cell types, both in terms of viral entry and replicative fitness. Interestingly, two spike mutations (L48S and A372T) that emerged in cells expressing low ACE2 levels increased receptor affinity, syncytia induction, and entry efficiency under low-ACE2 conditions. Our results demonstrate specific adaptation of the SARS-CoV-2 spike to different cell types and have implications for understanding SARS-CoV-2 tissue tropism and evolution.

E050 Angiotensin converting enzyme for the diagnosis of childhood sarcoidosis

Abstract Background/Aims Childhood sarcoidosis is a rare multisystem inflammatory granulomatous disease. The prevalence of sarcoidosis in children is unknown due to its rarity. A review of sarcoidosis in Denmark found an incidence in children < 15 years of 0.22-0.27 per 100 000/year. Diagnosis can be challenging given the varied presentations due to multisystem involvement. There is no one laboratory test that is diagnostic for sarcoidosis. Angiotensin converting enzyme (ACE) has been shown to be elevated in 50% of late-onset childhood sarcoidosis. Reference levels are laboratory and age dependent, and healthy children can have levels that are 40-50% higher than in adults. Our aim was to gain a better understanding of the use of ACE in clinical practice and to review its role in diagnosis and management of sarcoidosis. Methods We collated the list of all patients under 18 years who had ACE levels done at our hospital between 1/12/2021 and 30/11/2022 via clinical pathology. Electronic patient records were reviewed for all patients to gather information on demographics, and clinical symptoms. Results We had a total of 98 ACE blood tests done for 58 patients. Clinical notes and results were available for 34 of these patients with a total of 48 ACE results. Age range of patients was 3-17 years with a mean age of 12 years. 19 (56%) patients were female, 15 (44%) were male. 50% were of white ethnicity, 12% of black ethnicity, 3% Indian ethnicity, 3% Pakistani ethnicity, 3% Chinese ethnicity and 29% ethnicity not recorded. 45 were requested by in hospital specialties, 2 from other hospitals and 1 from a GP. Of those requested in hospital 73% had been requested by ophthalmology, rheumatology or dermatology, with the remainder requested by a range of other paediatric specialties. Results ranged from 11-195 U/L, with a median of 76 U/L. Hospital reference range is 13-64 U/L and 18 patients had results >64 U/L. Reference ranges for paediatric patients in literature is 29-112 U/L. 6 patients had a result>112U/L. One patient had a diagnosis of sarcoidosis. Following the initial results a further 4 years of results were analysed from 02/01/2018-30/11/2022. 10 further patients had ACE results >112U/L. Of these, none had sarcoidosis. Conclusion These results support that the diagnosis of sarcoidosis is rare. ACE results need to be interpreted being mindful that normal childhood ACE levels may be higher than the reference ranges given by hospitals, which may be based on adult ranges. There is need for more research in this area to ascertain diagnostic ACE levels and role of ACE in disease monitoring. I plan to lead a trainee multicentre retrospective project looking at the diagnosis of paediatric sarcoidosis, and within this review the role of ACE levels. Disclosure M.C. Mackay: None. S. Deepak: None. K. Warrier: None. S. Rangaraj: None.

OA28 The use of ACE and sIL2-R in a large tertiary cohort of patients with multi-system sarcoidosis

Abstract Background/Aims Sarcoidosis is a systemic inflammatory disorder characterised by the formation of non-caseating granulomas, and can affect almost any organ, ranging from self-limiting to a chronic and progressive disease. There are no validated biomarkers that help establish diagnosis or monitor disease progression. Serum Angiotensin-Converting Enzyme (ACE) is used in clinical practice despite some studies reporting a poor reflection of disease activity. Soluble interleukin 2 receptor (sIL-2R) is being used with increasing frequency and may be a useful tool in establishing diagnosis and monitoring disease progression. Our objectives were to evaluate the use of ACE and sIL2-R in a large tertiary cohort of patients with multisystem sarcoidosis. Methods This was an observational cohort study. Patients with a confirmed diagnosis of sarcoidosis at King’s College Hospital between 2013 and 2023 were identified. Demographics, symptoms onset, clinical features, ACE, sIL2-R, high-resolution computed tomography (HRCT), Positron emission tomography-computed tomography (PET-CT), histology and immunomodulating therapy were extracted from electronic health records. Cross sectional correlations between ACE and sIL2-R was assessed by Spearman’s correlation coefficient (rs). Results Data were extracted for 196 individuals diagnosed with sarcoidosis. The mean age was 55 (SD 16) with a female and black predominance (table 1). A prior exposure risk of silica or dust was identified in 5 individuals. At diagnosis the most frequently reported organ involvement was lung (65%), eye (20%), musculoskeletal (13%) and skin (12%). Organ involvement on PET-CT was seen in 77%. 22% had interstitial lung disease (ILD) confirmed on HRCT and 3% had myocarditis on cardiac MRI. Steroids were commenced in 56%, with a mean dose of 19mg (SD 13mg). The mean duration of follow up was 7 years (IQR 2.9-14.4), 11% developed symptoms suggestive of new organ involvement, 7% had PET-CT evidence of new organ involvement, 4% had evidence of ILD progression and 14% underwent re-initiation or escalation of steroid therapy. 42% (n = 82) had results for both sIL2-R and ACE biomarkers. The median ACE was 55u/L (IQR 40-83) and sIL2-R 1781ng/L (IQR 1328-2436). 50% (41/82) had a sIL2-R >1800ng/L and 59% (48/82) had an ACE >50u/L. Interestingly, 32% (13/41) with a sIL2-R >1800 had a normal ACE and 42% (20/41) with an ACE >50 had a normal sIL2-R results. sIL2-R correlated with ACE (rs = 0.34, p = 0.0018). There was no significant difference in ACE levels in those taking ACE inhibitors (n = 9) compared to those (n = 73) not: 55u/L (IQR 41-83) versus 39u/L (IQR 30-65) p = 0.30. Conclusion sIL2-R significantly correlated with serum ACE, although the rs value is not particularly strong, suggesting other factors may be influencing the relationship. These biomarkers represent different aspects of the disease; serum ACE reflects granulomatous inflammation whilst sIL2-R implies immune system activation and T-cell involvement, which may explain our findings. Disclosure M. Hughes: None. K. Bechman: Honoraria; UCB, Viforpharma. Grants/research support; NIHR, Versus Arthritis/Pfizer. R. Roy: None. M. Omar: None. D. Mehta: None. D. Nagra: None. S. Walsh: None. S.S. Birring: None. D.M. Sado: None. P.A. Brex: None. J. Galloway: Honoraria; Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB.

ACE Phenotyping in Human Blood and Tissues: Revelation of ACE Outliers and Sex Differences in ACE Sialylation.

Angiotensin-converting enzyme (ACE) metabolizes a number of important peptides participating in blood pressure regulation and vascular remodeling. Elevated ACE expression in tissues (which is generally reflected by blood ACE levels) is associated with an increased risk of cardiovascular diseases. Elevated blood ACE is also a marker for granulomatous diseases. Decreased blood ACE activity is becoming a new risk factor for Alzheimer's disease. We applied our novel approach-ACE phenotyping-to characterize pairs of tissues (lung, heart, lymph nodes) and serum ACE in 50 patients. ACE phenotyping includes (1) measurement of ACE activity with two substrates (ZPHL and HHL); (2) calculation of the ratio of hydrolysis of these substrates (ZPHL/HHL ratio); (3) determination of ACE immunoreactive protein levels using mAbs to ACE; and (4) ACE conformation with a set of mAbs to ACE. The ACE phenotyping approach in screening format with special attention to outliers, combined with analysis of sequencing data, allowed us to identify patient with a unique ACE phenotype related to decreased ability of inhibition of ACE activity by albumin, likely due to competition with high CCL18 in this patient for binding to ACE. We also confirmed recently discovered gender differences in sialylation of some glycosylation sites of ACE. ACE phenotyping is a promising new approach for the identification of ACE phenotype outliers with potential clinical significance, making it useful for screening in a personalized medicine approach.

Mathematical modelling of the influence of ACE I/D polymorphism on blood pressure and antihypertensive therapy

The angiotensin-converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism raises the possibility of personalising ACE inhibitor therapy to optimise its efficiency and reduce side effects in genetically distinct subgroups. However, the extent of its influence among these subgroups is unknown. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of the ACE I/D polymorphism on haemodynamic parameters in humans undergoing antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation and therefore, the lack of association between ACE I/D and blood pressure levels may be due to high ACE activity in specific populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship between ACE I/D and the efficacy of inhibitors of the renin–angiotensin–aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, while different ACE I/D genotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success and its predictive value is limited.

ACE2 and TMPRSS2 expression in patients before, during, and after SARS-CoV-2 infection.

During the SARS-CoV-2 pandemic angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) were constantly under the scientific spotlight, but most studies evaluated ACE2 and TMPRSS2 expression levels in patients infected by SARS-CoV-2. Thus, this study aimed to evaluate the expression levels of both proteins before, during, and after-infection. For that, nasopharyngeal samples from 26 patients were used to measure ACE2/TMPRSS2 ex-pression via qPCR. Symptomatic patients presented lower ACE2 expression levels before and after the infection than those in asymptomatic patients; however, these levels increased during SARS-CoV-2 infection. In addition, symptomatic patients presented higher expression levels of TMPRSS2 pre-infection, which decreased in the following periods. In summary, ACE2 and TMPRSS2 expression levels are potential risk factors for the development of symptomatic COVID-19, and the presence of SARS-CoV-2 potentially modulates those levels.

Endothelial factors and blood homocysteine level in adolescents with rheumatic diseases

It is known that the dysfunction of the endothelium has crucial role in many pathological conditions and underlines adverse cardiovascular events. The aim of our study was to determine biologically active substances in the blood that affect endothelial function and homocysteine level in adolescents with rheumatic diseases. Materials and methods. We examined 68 patients with rheumatic diseases, among them 25 patients with systemic lupus erythematosus (SLE) and 43 patients with juvenile idiopathic arthritis (JIA). Obtained results were compared with similar indicators of peers from the control group. All patients received basic therapy for 12 or more months at the time of examination. Biologically active substances (Homocysteine (Hcy), vascular endothelial growth factor (VEGF), high-sensitivity C-reactive protein (hs-CRP)) were studied by enzyme-linked immunosorbent assay, brain natriuretic peptide (NT-proBNP) by competitive immunoassay, and angiotensin-converting enzyme (ACE) by turbidimetric FAPGG kinetics method. Results. Patients with rheumatic diseases had a significantly higher level of BNP (p < 0.01). These changes were most significant in patients with SLE. The level of Hcy did not differ from the similar indicator of the control group, but in patients with SLE it was significantly higher (p < 0.01) than in patients with JIA. Conclusions. In patients with rheumatic diseases, biologically active substances level affecting the endothelium function depends on the disease. Biologically active substances affecting the function of the endothelium were within normal values. Thus, in children with SLE compared with JIA children, an increase in Hcy and NT-proBNP, and a decrease in ACE and hs-CRP protein were found. In children with JIA, normal levels of Hcy and ACE are accompanied by an increase in NT-proBNP and hs-CRP. In adolescents aged 10–18 years with SLE and JIA, multidirectional changes in biologically active substances and homocysteine, affecting the endothelial function of blood vessels were found.

Fibulin-1 promotes intimal hyperplasia after venous stent implantation through ACE mediated angiotensin II signaling

ObjectiveStent intimal hyperplasia leads to in stent restenosis and thrombosis. This study determined whether Fibulin-1 activity in smooth muscle cells (SMCs) contributes to stent restenosis or thrombosis. MethodsStent implantation was conducted in a pig model. Target vessel samples were stained and analyzed by protein mass spectrometry. Cell experiments and Fibulin-1 SMC specific knockout mice (Fbln1SMKO) were used to investigate the mechanism of Fibulin-1 induced SMC proliferation and thrombosis. ResultsSMC proliferation and phenotypic transition are the main pathological changes of intimal hyperplasia in venous stents. Protein mass spectrometry analysis revealed a total of 67 upregulated proteins and 39 downregulated proteins in intimal hyperplasia after stent implantation compared with normal iliac vein tissues. Among them, Fibulin-1 ranked among the top proteins altered. Fibulin-1 overexpressing human SMCs (Fibulin-1-hSMCs) showed increased migration and phenotypic switching from contractile to secretory type and Fibulin-1 inhibition decreased the activity of SMCs. Mechanistically, Fibulin-1-hSMCs displayed increased levels of angiotensin converting enzyme (ACE) expression and angiotensin II signaling. Inhibition of ACE or angiotensin II signaling alleviated the migration of Fibulin-1-hSMCs. Using Fibulin-1 SMC specific knockout mice (Fbln1SMKO) and venous thrombosis model, we demonstrated that Fibulin-1 deletion attenuated intimal SMCs proliferation and thrombosis. Further, Fibulin-1 concentration was high in iliac vein compression syndrome (IVCS) patients treated with stent and was an independent predictor of venous insufficiency. ConclusionsFibulin-1 promotes SMC proliferation partially through ACE secretion and angiotensin II signaling after stent implantation. Fibulin-1 plays a role in venous insufficiency syndrome, implicating the protein in the detection and treatment of IVCS.

The Relationship between Soluble Angiotensin-Converting Enzyme Level and Coronavirus Disease 2019 in Children: A Prospective Cohort Study

Abstract Objective Our objective was to investigate soluble angiotensin-converting enzyme (sACE) levels in pediatric patients with coronavirus disease 2019 (COVID-19) and to identify factors associated with the occurrence and severity of pediatric COVID-19. Methods This was a prospective cohort study conducted between April 2020 and July 2020. The study population consisted of 143 children (between 1 month and 18 years old), 103 of whom had COVID-19 and 40 of whom were negative for COVID-19 (randomly selected). The sACE levels and other laboratory data of all participants were measured at admission (day 0, baseline). Repeat measurements were performed in patients on the 5th day. Disease severity was documented at baseline and on the 5th day, and the change in severity between these time points was recorded. Results Age and sex distribution were similar in the two groups. At baseline, 31 (30.1%) of the patients were asymptomatic, 58 (56.3%) had mild disease, and 14 (13.6%) had moderate disease. Baseline sACE levels were similar in the groups (p = 0.120). Higher weight was independently associated with low sACE levels in children (p = 0.037). The sACE level of patients on the 5th day was significantly lower compared with baseline (p = 0.007). Patients who experienced a decrease in disease severity were compared with those who did not demonstrate a decrease. Baseline sACE levels were significantly lower in those who experienced decreased severity (p = 0.039). Multiple linear regression revealed that COVID-19 severity at baseline was independently associated with the low sACE level at baseline (p = 0.023). Conclusion Lower sACE at diagnosis was associated with COVID-19 severity in children. However, no strong evidence was found that could suggest the sACE level as an important predictor for the occurrence or severity of COVID-19 in children.

Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors.

DPP4 (Dipeptidyl-peptidase 4) a versatile protease, emerges as a prominent player in soluble and membrane-bound forms. Its heightened expression has been intimately linked to the initiation and severity of diverse autoimmune diseases, spanning rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory bowel disease, autoimmune diabetes, and even SARS-CoV-2 infection. Operating as a co-stimulator of T cell activity, DPP4 propels T cell proliferation by binding adenosine deaminase (ADA), thereby augmenting the breakdown of adenosine-an influential inhibitor of T cell proliferation. However, the discovery of a wide range of DPP4 inhibitors has shown promise in alleviating these diseases' signs, symptoms, and severity. The available DPP4 inhibitors have demonstrated significant effectiveness in blocking DPP4 activity. Based on the characterization of their binding mechanisms, three distinct groups of DPP4 inhibitors have been identified: saxagliptin, alogliptin, and sitagliptin, each representing a different class. Elevated levels of angiotensin-converting enzyme 2 (ACE2) expression are associated with producing various coronavirus peptidases. With its anti-inflammatory properties, Sitagliptin may assist COVID-19 patients in preventing and managing cytokine storms. This comprehensive review delves into the burgeoning realm of DPP4 inhibitors as therapeutic interventions for diverse autoimmune diseases. With a discerning focus on their efficacy, the investigation sheds light on their remarkable capacity to alleviate the burdensome signs and symptoms intricately linked to these conditions.

Association Between COVID-19 and Hypertension

Chinese authorities reported the first human-to-animal SARS-CoV-2 transmission in late 2019. The virus then quickly spread from person to person throughout the world and increased the mortality rate of those with underlying illnesses, particularly hypertension. After attaching the virus to a special receptor, that is, angiotensin-converting enzyme-2 (ACE2), ACE2 degrades angiotensin 2 (Ang2). Ang2 as a modulator of blood pressure and a vasoconstrictor plays an adverse regulatory role in the renin-angiotensin system (RAS). Additionally, it changes Ang2 into Ang1-7, which functions as an antioxidant and an anti-inflammatory factor. Infection with SARSCoV-2 lowers ACE2 levels in hypertensive patients because the virus binds to the blood vessel, preventing Ang II degradation. As a result, complications related to hypertension increase, and the pumping of blood from the lungs to the left atrium decreases. Additionally, there is a decrease in the final product, Ang1-7, and the concomitant anti-inflammatory action is lost. The virus grows, multiplies, damages lung cells, causing inflammation in immune cells and cytokines and expanding lung tissue. This ultimately leads to lung injury, a decline in the oxygen supply, and death. The management of hypertensive patients can prevent infection in this population and reduce mortality with proper oxygen therapy and probably exogenous ACE2 supplementation.

Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.

Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1atm, 2weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests. Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P<0.001; Soleus: 11.5% reduction in weight, P<0.001) and weakness (10.0% reduction in peak-isometric torque, P<0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P<0.001), and incomplete strength recovery (92.3% of pre-injury levels, P<0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P<0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P<0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P<0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P<0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy. Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

Differences in vascular endothelial function and serum proteome between obese people with phlegm-dampness constitution and balanced constitution.

To evaluate the extent of vascular endothelial dysfunction and preliminary identify serum protein biomarkers associated with obese individuals at risk for cardiovascular disease (CVD). Fifteen obese volunteers with the phlegm-dampness constitution or balanced constitution were recruited for this study respectively. The clinical baseline data was collected, and the vascular endothelial function was evaluated using the EndoPATTM. Blood samples were collected for the serum proteome analysis. The differences in the serum protein expression levels between the two groups were detected and the protein interaction network analysis, correlation analysis, receiver operating characteristic (ROC) curve analysis, and random forest model investigation were conducted. There were no statistical differences found in the baseline data. For vascular endothelial function, the reactive hyperemia index (RHI) of the phlegm-dampness constitution obese group was significantly lower than that of the balanced constitution obese group (1.46 ± 0.30 vs 2.82 ± 0.78, P < 0.0001), indicating vascular endothelial dysfunction. There are 66 differentially expressed serum proteins between the two groups. apolipoprotein A2 (ApoA2), angiotensin-converting enzyme 2 (ACE-2), interleukin-33 (IL-33), and forkhead box P3 (FoxP3) showed significant differences and area under curve values of their ROC curves were greater than 0.7 and correlated significantly with RHI. Vascular endothelial dysfunction was present in the phlegm-dampness constitution obese group. Thus, alterations in the expression levels of key serum proteins, including ApoA2, ACE-2, IL-33, and FoxP3 could serve as potential biomarkers in the obese population at risk of CVD.

Sarcoidosis Masquerading as Miliary Tuberculosis: A Case Report

A miliary nodular pattern of the lungs is an unusual presentation of sarcoidosis. Diagnosis of this condition can be challenging and requires exclusion of other lung pathology. A 47-year-old African American male presented to his doctor with a complaint of unintentional weight loss, exertional dyspnea and cough. The patient had a history of chronic smoking as well as recent incarceration. A miliary nodular pattern was found on CT scan of the lungs in a random distribution (with prominent peri-lymphatic distribution). HIV was ruled out. Tuberculosis (TB) and fungal infections were ruled out by tissue specimens and cultures from bronchoalveolar washings. Non-caseating granulomas on tissue specimens, peripheral smear lymphopenia and an elevated angiotensin converting enzyme (ACE) level were the positive findings on pathology and labs. The patient responded to a tapering course of oral steroids. This case demonstrates one of the unusual clinical presentations of sarcoidosis. Sarcoidosis is an autoimmune condition with predilection for middle aged African American patients.