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Animal venoms are multifaceted mixtures, including proteins, peptides and enzymes produced by animals in defense, predation and digestion. These molecules have been investigated concerning their molecular mechanisms associated and possible pharmacological applications. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. Scorpaena plumieri is the most venomous fish in the Brazilian fauna and is responsible for relatively frequent accidents involving anglers and bathers. In humans, its venom causes edema, erythema, ecchymoses, nausea, vomiting, and syncope. Recently, the presence of a type of angiotensin converting enzyme (ACE) activity in the venom of Thalassophryne nattereri and Scorpaena plumieri, endemic fishes in northeastern coast of Brazil, has been described. The ACE converts angiotensin I (Ang I) into angiotensin II (Ang II) and inactivates bradykinin, there by regulating blood pressure and electrolyte homeostasis, however, their function in these venoms remains an unknown. This article provides an overview of the current knowledge on ACE in the venoms of Thalassophryne nattereri and Scorpaena plumier . [ABSTRACT FROM AUTHOR]

Background Angiotensin-converting enzyme ( ACE) downregulates the activity of bradykinin, a potent proinflammatory and immunostimulatory peptide liberated from an internal portion of kininogens. Here, we asked whether periodontitis is worsened in patients under antihypertensive treatment with ACE inhibitors. Methods Periodontal parameters were recorded from 30 individuals taking ACE inhibitors (case) and 35 taking a non- ACE inhibitor medication (control). Data were analyzed by nonparametric and parametric statistical tests. Results Most sociodemographic figures were similar in both groups. However, family income was statistically higher in the control group, and the percentage of sites with visible plaque (PL) was statistically higher in the case group ( P = 0.043 and P = 0.005, respectively). The prevalence of individuals with chronic periodontitis varied from 31.5% in the control group to 63.4% in the case group ( P = 0.001). Patients in the case group presented a 3.2-fold higher risk of having sites with pocket depth ≥5 mm and a 2.9-fold higher risk of having sites with clinical attachment loss ≥5 mm in comparison with those in the control group ( P = 0.009 and P = 0.001, respectively; adjusted for family income and visible PL). Conclusion Angiotensin-converting enzyme inhibitors may increase the prevalence and extent of chronic periodontitis in Brazilian patients. [ABSTRACT FROM AUTHOR]

Background: Hereditary angioedema can be caused by C1-Inhibitor (C1-INH) deficiency and/or dysfunction (HAE-1/2) or can occur in patients with normal C1-INH (HAE nC1-INH)., Methods: The Icatibant Outcome Survey (IOS; NCT01034969) registry monitors the safety and effectiveness of icatibant for treating acute angioedema., Objective: Present findings from Brazilian patients with HAE-1/2 and HAE nC1-INH participating in IOS., Results: 42 patients were enrolled (HAE-1/2, n = 26; HAE nC1-INH, n = 16). Median age at symptom onset was significantly lower with HAE-1/2 vs. HAE nC1-INH (10.0 vs. 16.5y, respectively; p = 0.0105), whereas median age at diagnosis (31.1 vs. 40.9y; p = 0.1276) and the median time between symptom onset and diagnosis (15.0 vs. 23.8y; p = 0.6680) were numerically lower vs. HAE nC1-INH, respectively. One icatibant dose was used for > 95% of HAE attacks. Median (range) time-to-event outcomes were shorter for patients with HAE nC1-INH vs. HAE-1/2, including time to first administration (0.5 [0-96.0] vs. 1.0 [0-94.0]h, respectively), time from first administration to complete resolution (1.0 [0-88.0] vs. 5.5 [0-96.0]h, respectively), and total attack duration (7.0 [0.3-99.0] vs. 18.5 [0.1-100.0]h, respectively). Mean (SD) time from attack onset to resolution was significantly shorter for patients with HAE nC1-INH vs. HAE-1/2 (9.8 [18.7] vs. 19.6 [24.0]h, respectively; p = 0.0174). 83 adverse events (AEs) in 42 patients were reported; most were mild (66.3%) or moderate (13.3%) and non-serious (75.9%). The most common icatibant-related AE was injection site erythema (HAE-1/2, 34.6%; HAE nC1-INH, 18.8%)., Study Limitations: This was an observational study without a treatment comparator and that relied on patient recall., Conclusions: Findings demonstrate effectiveness and tolerability of icatibant in Brazilian HAE patients., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Some mechanisms have been proposed to explain the role of bradykinin on glucose homeostasis and some studies reported that the BDKRB2 +9/-9 polymorphism was associated to the transcriptional activity of the receptor. In this scenario, the main aim of this study was to evaluate the association of the BDKRB2 +9/-9 polymorphism with diabetes mellitus risk in the Brazilian general population. This study included 1,032 subjects of the general urban population. Anthropometrical, blood pressure, biochemical, and genotype analyses for the BDKRB2 +9/-9 bp insertion/deletion polymorphism were performed. Individuals carrying +9/+9 or +9/-9 genotypes had higher glucose values (84.5mg/dL versus 80.6mg/dL, resp.) and higher frequency of diabetes mellitus (7.6% versus 3.6%, resp.) compared to individuals carrying -9/-9, adjusting for age and gender. In addition, higher diabetes mellitus risk was associated to presence of the +9/+9 or +9/-9 genotypes (OR= 1.91; 95% CI = 1.09-4.19; P = 0.03). Our data suggest that the BDKRB2 +9/-9 polymorphismmay act as a geneticmodulator of glucose homeostasis. It was previously associated to insulin sensitivity, glucose uptake, and insulin secretion, and, in this study, data suggest that the polymorphism may increase susceptibility to chronic metabolic conditions such as diabetes in the Brazilian population. [ABSTRACT FROM AUTHOR]

Background: Primary angioedema (PA) is a complex disorder, presenting multiple hereditary (hereditary angioedema) and acquired subtypes (acquired angioedema). Despite a very similar clinical presentation among subtypes, the differential diagnosis is limited by the difficulty to identify bradykinin-mediated PA and the lack of specific biomarkers., Objectives: To report the clinical and genetic features of Brazilian patients with PA., Methods: Brazilian patients referred from 50 centers were diagnosed on the basis of clinical symptoms, C1 inhibitor (C1-INH) and C4 plasma measurements, and DNA sequencing of genes associated with hereditary angioedema., Results: We characterized 92 patients with acquired angioedema and 425 with HAE: 125 with C1-INH deficiency, 180 with F12 mutations, and 120 of unknown cause. Thirty-one different mutations were identified in SERPING1 and 2 in F12, in addition to 2 mutations of uncertain significance in the ANGPT1 gene. The molecular diagnosis was decisive for 34 patients with HAE without family history, and for 39% of patients with inconsistent biochemical measurements. The median delay in diagnosis was 10 years, with a maximum of 18 years for HAE with C1-INH deficiency. Androgens and tranexamic acid were the most used drugs for long-term prophylaxis in all the PA subtypes, and they were used on demand by 15% of patients. Only 10% of patients reported the use of specific medication for HAE during attacks., Conclusions: Our analysis exposes a broad picture of PA diagnosis and management in a developing country. Complement measurements presented considerable inconsistencies, increasing the diagnosis delay, while patients with PA with normal C1-INH remain with an inaccurate diagnosis and unspecific treatment., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19., Methods: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy., Discussion: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates., Trial Registration: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

The venom of marine animals is a rich source of compounds with remarkable functional specificity and diversity. Thalassophryne nattereri is a small venomous fish inhabiting the northern and northeastern coast of Brazil, and represents a relatively frequent cause of injuries. Its venom causes severe inflammatory response followed frequently by the necrosis of the affected area. This venom presents characterized components such as proteases (Natterins 1-4) and a lectin (Nattectin) with complex effects on the human organism. A specific inhibitor of tissue kallikrein (TKI) reduces the nociception and the edema caused by the venom in mice. Our study sought to investigate the proteolytic activities against vasopeptides Angiotensin I, Angiotensin II, Angiotensin 1-9 and Bradykinin. The venom indicated angiotensin conversion against angiotensin I, as well as kininase against bradykinin. Captopril conducted the total inhibition of the converting activity, featuring the first report of ACE activity in fish venoms., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nidularium procerum, a common plant of the Brazilian flora, has not yet been studied for its pharmacological properties. We report here that extracts of N. procerum show both analgesic and anti-inflammatory properties. Oral (p.o.) or intraperitoneal (i.p.) administration of an aqueous crude extract from leaves of N. procerum (LAE) inhibited the writhing reaction induced by acetic acid (ED50 value = 0.2 mg/kg body weight, i.p.) in a dose-dependent manner. This analgesic property was confirmed in rats using two different models of bradykinin-induced hyperalgesia; there was 75% inhibition of pain in the modified Hargreaves assay, and 100% inhibition in the classical Hargreaves assay. This potent analgesic effect was not blocked by naloxone, nor was it observed in the hot plate model, indicating that the analgesic effect is not associated with the activation of opioid receptors in the central nervous system. By contrast, we found that LAE (0.02 microg/ml) selectively inhibited prostaglandin E2 production by cyclooxygenase (COX)-2, but not COX-1, which is a plausible mechanism for the analgesic effect. A crude methanol extract from the leaves also showed similar analgesic activity. An identical extract from the roots of N. procerum did not, however, block acetic acid-induced writhes, indicating that the analgesic compounds are concentrated in the leaves. Finally, we found that LAE inhibited an inflammatory reaction induced by lipopolysaccharide in the pleural cavity of mice.