Analyzing the interaction of human ACE2 and RBD of spike protein of SARS-CoV-2 in perspective of Omicron variant

The newly identified Omicron (B.1.1.529) variant of Severe Acute Respiratory Syndrome Voronavirus 2 (SARS-CoV-2) has steered concerns across the world due to the possession of large number of mutations leading to high infectivity and vaccine escape potential. The Omicron variant houses 32 mutations in S protein alone. The viral infectivity is determined mainly by the ability of spike (S) protein receptor binding domain (RBD) to bind to the human Angiotensin I Converting Enzyme 2 (hACE2) receptor. In this paper, the interaction of the RBDs of SARS-CoV-2 variants with hACE2 was analyzed by using protein-protein docking and compared with the novel Omicron variant. Our findings reveal that the Omicron RBD interacts strongly with hACE2 receptor via unique amino acid residues as compared to the Wuhan and many other variants. However, the interacting residues of RBD are found to be the same in Lamda (C.37) variant. These unique binding of Omicron RBD with hACE2 suggests an increased potential of infectivity and vaccine evasion potential of the new variant. The evolutionary drive of the SARS-CoV-2 may not be exclusively driven by RBD variants but surely provides for the platform for emergence of new variants.

The functional state of the kallikrein-kinin and renin-angiotensin-aldosterone systems in patients with localized kidney cancer

Introduction. The development of a malignant tumor naturally affects renal function. During tumor formation, the renal tissue is destructed either by direct invasion into the parenchyma, or by mechanical change in the renal architecture caused by compression of the renal parenchyma, collecting ducts, tubules, and nephrons. In addition, a tumor can secrete biologically active substances, which have an indirect negative influence the functional state of the organ. Currently, it has been established that kallikrein-kinin and renin-angiotensin-aldosterone systems play an important role in the development of nephropathy of various genesis. At the same time, these systems' role in the development of renal function disorders in the setting of tumor damage has not yet been studied.Purpose of the study. To study changes in the components of the kallikrein-kinin and renin-angiotensin-aldosterone systems in the case of localized kidney cancer.Materials and methods. Forty-five patients diagnosed with T1N0M0 kidney cancer and 13 relatively healthy patients without cancer were examined. The determination of the components of the systems under study was carried out by the kinetic method after chromatography of blood plasma and urine using DEAE-Sephadex A-50 (Amersham Biosciences Corp., Sweden). The indices of angiotensin-1, renin, aldosterone, and cortisol were studied by an indirect method of radioimmunoassay. Statistical processing was carried out using Statistica 8.0 software (StatSoft Inc., IBM Corp., USA) by means of the Student-Fisher test (p < 0.05).Results. The development of kidney cancer is accompanied by a 2.3-fold increase in the activity of kallikrein and other trypsin proteases with a significant deficiency of their inhibitors (p < 0,05). Against this background, there is a 1.3-fold decrease in the cortisol/renin ratio from a 2.9-fold and 2.3-fold increase in the values of the renin/angiotensin-I and cortisol/angiotensin-I interaction ratios, respectively, compared with the normal values of these indicators (p < 0,05).Conclusions. Renal cell carcinoma is accompanied by trespassing of local metabolism with the formation of tubulointerstitial dysfunction and a shift of the proteinase-inhibitory balance towards proteolytic activation.

Localization and Distribution of Testicular Angiotensin I Converting Enzyme (ACE) in Neck and Mid-Piece of Spermatozoa from Infertile Men in Relation to Sperm Motility

Testicular angiotensin converting enzyme (ACE) is known to play an essential role in the male reproduction and fertility. Data about tACE in cases of male infertility are quite scarce, and in this respect we aimed to study localization and distribution of tACE protein in the neck and mid-piece of spermatozoa from pathological samples in relation to sperm motility. The enzyme expression during capacitation and acrosome reaction was quantitatively assessed. In human ejaculated spermatozoa tACE is localized on sperm plasma membrane of the head, the neck and mid-piece of the tail. The immunoreactivity becomes stronger in capacitated spermatozoa followed by a decrease in acrosome reacted sperm. In different cases of semen pathology (oligozoospermia, asthenozoospermia and teratozoospermia) fluorescent signals in the neck and mid-piece are in punctate manner whereas in normozoospermia they were uniformly distributed. The expression area of tACE the neck and mid-piece was decreased in ejaculated and capacitated sperm from pathological semen samples compared to normospermia. Significant positive correlation was established between tACE area and progressive sperm motility, whereas with immotile sperm the correlation was negative. Our data suggest that proper distribution of tACE in the neck and mid-piece is required for normal sperm motility that could be used as a novel biomarker for male infertility.

A Novel Angiotensin-I-Converting Enzyme (ACE) Inhibitory Peptide from Takifugu flavidus

Alcalase, neutral protease, and pepsin were used to hydrolyze the skin of Takifugu flavidus. The T. flavidus hydrolysates (TFHs) with the maximum degree of hydrolysis (DH) and angiotensin-I-converting enzyme (ACE)-inhibitory activity were selected and then ultra-filtered to obtain fractions with components of different molecular weights (MWs) (<1, 1–3, 3–10, 10–50, and >50 kDa). The components with MWs < 1 kDa showed the strongest ACE-inhibitory activity with a half-maximal inhibitory concentration (IC50) of 0.58 mg/mL. Purification and identification using semi-preparative liquid chromatography, Sephadex G-15 gel chromatography, RP-HPLC, and LC–MS/MS yielded one new potential ACE-inhibitory peptide, PPLLFAAL (non-competitive suppression mode; IC50 of 28 μmmol·L−1). Molecular docking and molecular dynamics simulations indicated that the peptides should bind well to ACE and interact with amino acid residues and the zinc ion at the ACE active site. Furthermore, a short-term assay of antihypertensive activity in spontaneously hypertensive rats (SHRs) revealed that PPLLFAAL could significantly decrease the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of SHRs after intravenous administration. These results suggested that PPLLFAAL may have potential applications in functional foods or pharmaceuticals as an antihypertensive agent.

Haemangioma: A Study of the Biology

<p>Infantile haemangioma (IH), considered a primary tumour of the microvasculature, is the most common tumour of infancy affecting about 10% of Caucasian infants. IH predominantly affects white, female and premature infants. IH typically undergoes an initial rapid proliferation during infancy (proliferative phase) characterised by aggressive angiogenesis, followed by spontaneous involution over the next 1-5 years (involuting phase) and continued improvement up to 10 years (involuted phase), often with a fibro-fatty residuum. IH consists of cells of various lineages, with the presence of mesenchymal stem cells, endothelial progenitor cells, endothelial cells, myeloid haematopoietic cells, and pericytes. This thesis demonstrates the expression of primitive (stem/progenitor cell) markers on the endothelium of IH. The expression of the transcription factors brachyury, Tal-1 and GATA-2, along with the demonstration of erythropoiesis in IH explants in vitro supports the hypothesis that IH consists of a primitive endothelium similar to an embryonic haemogenic endothelium. The expression of the erythropoietin receptor and haemoglobin zeta chain by the endothelium of IH further strengthens the notion that IH is a haemogenic endothelium. Consistent with the primitive embryonic origin, the expression of the placental markers human chorionic gonadotrophin (hCG) and human placenta lactogen (hPL), but not cytokeratin 7 (CK7) or human leucocyte antigen- G (HLA-G) by the endothelium in IH, supports a placental chorionic villous mesenchymal core cell, and not a trophoblast, origin for IH. IH thus has an extraembryonically derived primitive mesodermal origin. This primitive mesoderm is able to account for the haemogenic endothelium phenotype of the endothelium of proliferating IH microvessels with its capacity for both erythropoietic and mesenchymal differentiation. Additionally, data are presented to show that IH expresses key components of the renin-angiotensin system (RAS), angiotensin converting enzyme (ACE), angiotensin II (ATII), angiotensin receptor 2 (ATR2). Cultured IH-derived stem cells can be induced to proliferate and form blast colonies in response to ATII treatment. The crucial regulatory role of RAS in the proliferation and differentiation of the stem/progenitor cell population within IH accounts for the natural progression of IH. A model is proposed to provide a rational explanation for the serendipiditous discovery of the dramatic effect that the β-blocker, Propranolol has in accelerating involution of IH. The hypothesis that Propranolol exerts its action on IH through modulation of the RAS by blocking renin activity and preventing the conversion of angiotensinogen to angiotensin I, thereby reducing ATII levels, has led to a clinical trial using Captopril, an ACE inhibitor in the treatment of problematic proliferating IH. The observed accelerated involution of IH by Captopril which blocks the conversion of angiotensin I to ATII confirms a key regulatory role for RAS in the biology of IH This discovery underpins the development of potentially safer and novel treatment modalities for this enigmatic condition.</p>

Haemangioma: A Study of the Biology

<p>Infantile haemangioma (IH), considered a primary tumour of the microvasculature, is the most common tumour of infancy affecting about 10% of Caucasian infants. IH predominantly affects white, female and premature infants. IH typically undergoes an initial rapid proliferation during infancy (proliferative phase) characterised by aggressive angiogenesis, followed by spontaneous involution over the next 1-5 years (involuting phase) and continued improvement up to 10 years (involuted phase), often with a fibro-fatty residuum. IH consists of cells of various lineages, with the presence of mesenchymal stem cells, endothelial progenitor cells, endothelial cells, myeloid haematopoietic cells, and pericytes. This thesis demonstrates the expression of primitive (stem/progenitor cell) markers on the endothelium of IH. The expression of the transcription factors brachyury, Tal-1 and GATA-2, along with the demonstration of erythropoiesis in IH explants in vitro supports the hypothesis that IH consists of a primitive endothelium similar to an embryonic haemogenic endothelium. The expression of the erythropoietin receptor and haemoglobin zeta chain by the endothelium of IH further strengthens the notion that IH is a haemogenic endothelium. Consistent with the primitive embryonic origin, the expression of the placental markers human chorionic gonadotrophin (hCG) and human placenta lactogen (hPL), but not cytokeratin 7 (CK7) or human leucocyte antigen- G (HLA-G) by the endothelium in IH, supports a placental chorionic villous mesenchymal core cell, and not a trophoblast, origin for IH. IH thus has an extraembryonically derived primitive mesodermal origin. This primitive mesoderm is able to account for the haemogenic endothelium phenotype of the endothelium of proliferating IH microvessels with its capacity for both erythropoietic and mesenchymal differentiation. Additionally, data are presented to show that IH expresses key components of the renin-angiotensin system (RAS), angiotensin converting enzyme (ACE), angiotensin II (ATII), angiotensin receptor 2 (ATR2). Cultured IH-derived stem cells can be induced to proliferate and form blast colonies in response to ATII treatment. The crucial regulatory role of RAS in the proliferation and differentiation of the stem/progenitor cell population within IH accounts for the natural progression of IH. A model is proposed to provide a rational explanation for the serendipiditous discovery of the dramatic effect that the β-blocker, Propranolol has in accelerating involution of IH. The hypothesis that Propranolol exerts its action on IH through modulation of the RAS by blocking renin activity and preventing the conversion of angiotensinogen to angiotensin I, thereby reducing ATII levels, has led to a clinical trial using Captopril, an ACE inhibitor in the treatment of problematic proliferating IH. The observed accelerated involution of IH by Captopril which blocks the conversion of angiotensin I to ATII confirms a key regulatory role for RAS in the biology of IH This discovery underpins the development of potentially safer and novel treatment modalities for this enigmatic condition.</p>