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Biochemical Genetics Jan 2024The renin-angiotensin-aldosterone system has an indispensable function in the uteroplacental circulation, placental growth, and blood pressure optimization. The...
The renin-angiotensin-aldosterone system has an indispensable function in the uteroplacental circulation, placental growth, and blood pressure optimization. The angiotensin I converting enzyme (ACE) gene is a critical integrator for electrolyte balance, and water retention, along with inhibiting preeclampsia. The main goal of this pertaining study is to assess the contribution of ACE*(Ins/Del) variant with the susceptibility for preeclampsia with focus on the severity of the disease among gestational hypertensive women. This retrospective study included 225 participants [125 PE gestational women, and 100 normotensive healthy controls] matching with age, and geographical region. PE women classified into 82 early-onset PE women, accompanied with 43 late-onset PE women. Additionally, PE women categorized into 59 mild PE women, together with 66 severe PE women. The genotyping and characterization of ACE*(Ins/Del) variant were applied using the PCR technique. Our findings indicated higher frequency of the ACE*(Del/Del) genotype and ACE*(D allele) with elevated risk of preeclampsia compared to normotensive controls under recessive (OR = 2.09, and p-value = 0.007), and allelic (OR = 1.75, and p-value = 0.012) models. In addition, testing logistic regression revealed that the levels of endothelin-1 and malondialdehyde exposed significant difference for the ACE*(Del/Del) genotype among early-onset and late-onset PE women (p-value = 0.024, and 0.23, respectively). Furthermore, carriers of the ACE*(Del/Del) genotype observed statistically significant with lower sodium concentrations among severe PE women (p-value = 0.034). The ACE*(Del/Del) genotype and ACE*(D allele) were associated with increased risk preeclampsia among gestational women. Furthermore, early-onset PE and late-onset PE were correlated with endothelin-1 and malondialdehyde concentrations among Egyptian women.
PubMed: 38219243
DOI: 10.1007/s10528-023-10620-5 -
International Journal of Molecular... Dec 2023Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity...
Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model.
Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.
Topics: Animals; Mice; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Antiviral Agents; Chymases; Diabetes Mellitus; Diabetic Nephropathies; Diet, High-Fat; Disease Models, Animal; Mice, Knockout; Peptide Hormones; Renin-Angiotensin System; Serine Proteases
PubMed: 38203500
DOI: 10.3390/ijms25010329 -
ACS Omega Dec 2023Macroalgal proteins were extracted from (URPE) (green), (PPPE) (brown), and (LOPE) (red) using ultrasound-assisted enzymatic extraction, which is one of the green...
Macroalgal proteins were extracted from (URPE) (green), (PPPE) (brown), and (LOPE) (red) using ultrasound-assisted enzymatic extraction, which is one of the green extraction technologies. Techno-functional, characteristic, and digestibility properties, and biological activities including antioxidant (AOA) and angiotensin-I converting enzyme (ACE-I) inhibitory activities were also investigated. According to the results, the extraction yield (EY) (94.74%) was detected in the extraction of , followed by and . PPPE showed the highest ACE-I inhibitory activity before digestion. In contrast to PPPE, LOPE (20.90 ± 0.00%) and URPE (20.20 ± 0.00%) showed higher ACE-I inhibitory activity after digestion. The highest total phenolic content (TPC) (77.86 ± 1.00 mg GAE/g) was determined in LOPE. On the other hand, the highest AOA (74.69 ± 1.78 mg TE/g) and AOA (251.29 ± 5.0 mg TE/g) were detected in PPPE. After digestion, LOPE had the highest TPC (22.11 ± 2.18 mg GAE/g), AOA (8.41 ± 0.06 mg TE/g), and AOA (88.32 ± 0.65 mg TE/g) ( < 0.05). protein digestibility of three macroalgal protein extracts ranged from 84.35 ± 2.01% to 94.09 ± 0.00% ( < 0.05). Three macroalgae showed high oil holding capacity (OHC), especially PPPE (410.13 ± 16.37%) ( < 0.05), but they showed minimum foaming and emulsifying properties. The quality of the extracted macroalgal proteins was assessed using FTIR, SDS-PAGE, and DSC analyses. According to our findings, the method applied for macroalgal protein extraction could have a potential the promise of ultrasonication application as an environmentally friendly technology for food industry. Moreover, URPE, PPPE, and LOPE from sustainable sources may be attractive in terms of nourishment for people because of their digestibility, antioxidant properties, and ACE-I inhibitory activities.
PubMed: 38162757
DOI: 10.1021/acsomega.3c05041 -
European Journal of Pharmacology Mar 2024The angiotensin (Ang)-(1-12)/Ang II pathway contributes to cardiac pathology. However, its involvement in the development of peripheral endothelial dysfunction...
The angiotensin (Ang)-(1-12)/Ang II pathway contributes to cardiac pathology. However, its involvement in the development of peripheral endothelial dysfunction associated with heart failure (HF) remains unknown. Therefore, this study aimed to characterise the effect of exogenous Ang-(1-12) and its conversion to Ang II on endothelial function using the murine model of HF (Tgαq*44 mice), focusing on the role of chymase and vascular-derived thromboxane A (TXA). Ex vivo myographic assessments of isolated aorta showed impaired endothelium-dependent vasodilation in late-stage HF in 12-month-old Tgαq*44 mice. However, endothelium-dependent vasodilation was fully preserved in the early stage of HF in 4-month-old Tgαq*44 mice and 4- and 12-month-old FVB control mice. Ang-(1-12) impaired endothelium-dependent vasodilation in 4- and 12-month-old Tgαq*44 mice, that was associated with increased Ang II production. The chymase inhibitor chymostatin did not inhibit this response. Interestingly, TXA production reflected by TXB measurement was upregulated in response to Ang-(1-12) and Ang II in aortic rings isolated from 12-month-old Tgαq*44 mice but not from 4-month-old Tgαq*44 mice or age-matched FVB mice. Furthermore, in vivo magnetic resonance imaging showed that Ang-(1-12) impaired endothelium-dependent vasodilation in the aorta of Tgαq*44 mice and FVB mice. However, this response was inhibited by angiotensin I converting enzyme (ACE) inhibitor; perindopril, angiotensin II receptor type 1 (AT) antagonist; losartan and TXA receptor (TP) antagonist-picotamide in 12-month-old-Tgαq*44 mice only. In conclusion, the chymase-independent vascular Ang-(1-12)/Ang II pathway and subsequent TXA overactivity contribute to systemic endothelial dysfunction in the late stage of HF in Tgαq*44 mice. Therefore, the vascular TXA receptor represents a pharmacotherapeutic target to improve peripheral endothelial dysfunction in chronic HF.
Topics: Animals; Mice; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chymases; Disease Models, Animal; Heart Failure; Mice, Inbred Strains; Vascular Diseases
PubMed: 38158114
DOI: 10.1016/j.ejphar.2023.176296 -
American Journal of Physiology. Renal... Feb 2024Dyslipidemia, with changes in plasma membrane (PM) composition, is associated with hypertension, while rising PM cholesterol induces Na channel activity. We hypothesize...
Dyslipidemia, with changes in plasma membrane (PM) composition, is associated with hypertension, while rising PM cholesterol induces Na channel activity. We hypothesize that ablation of renal tubular ABCA1, a cholesterol efflux protein, leads to cholesterol- and Na-dependent changes in blood pressure (BP). Transgenic mice () expressing a doxycycline (dox)-inducible CRE recombinase were bred with mice expressing floxed ABCA1 to generate renal tubules deficient in ABCA1 (ABCA1FF). Tail-cuff systolic BP (SBP) was measured in mice on specific diets. Immunoblotting was performed on whole and PM protein lysates of kidney from mice completing experimental diets. Cortical PM of ABCA1FF showed reduced ABCA1 (60 ± 28%; = 10, < 0.05) compared with wild-type littermates (WT; = 9). Tail-cuff SBP of ABCA1FF ( = 11) was not only greater post dox, but also during cholesterol or high Na feeding ( < 0.05) compared with WT mice ( = 15). A Na-deficient diet abolished the difference, while 6 wk of cholesterol diet raised SBP in ABCA1FF compared with mice before cholesterol feeding ( < 0.05). No difference in α-ENaC protein abundance was noted in kidney lysate; however, γ-ENaC increased in ABCA1FF mice versus WT mice. In kidney membranes, NKCC2 abundance was greater in ABCA1FF versus WT mice. Cortical lysates of ABCA1FF mouse kidneys expressed less renin and angiotensin I receptor than WT mouse kidneys. Furosemide injection induced a greater diuretic effect in ABCA1FF ( = 7; 45.2 ± 8.7 µL/g body wt) versus WT ( = 7; 33.1 ± 6.9 µL/g body wt; < 0.05) but amiloride did not. Tubular ABCA1 deficiency induces cholesterol-dependent rise in SBP and modest Na sensitivity of SBP, which we speculate is partly related to Na transporters and channels. Cholesterol has been linked to greater Na channel activity in kidney cells, which may predispose to systemic hypertension. We showed that when ABCA1, a protein that removes cholesterol from tissues, is ablated from mouse kidneys, systemic blood pressure is greater than normal mice. Dietary cholesterol further increases blood pressure in transgenic mice, whereas low dietary salt intake reduced blood pressure to that of normal mice. Thus, we speculate that diseases and pharmaceuticals that reduce renal ABCA1 expression, like diabetes and calcineurin inhibitors, respectively, contribute to the prominence of hypertension in their clinical presentation.
Topics: Animals; Male; Mice; Blood Pressure; Cholesterol; Epithelial Sodium Channels; Hypertension; Mice, Knockout; Mice, Transgenic; Sodium
PubMed: 38153852
DOI: 10.1152/ajprenal.00154.2023 -
Naunyn-Schmiedeberg's Archives of... Jul 2024Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened...
Systemic vascular endothelial growth factor (VEGF) blockade has been the top adjunctive chemotherapy since 1990. Anti-VEGF therapy has also been associated with worsened renal function in some patients. However, the association between patient outcomes and use of intravitreal VEGF inhibitors remains controversial. Thus, it is necessary to determine the action mechanism and long-term renal effects of ranibizumab. The National Health Insurance Research Database (NHIRD) is one of the largest global databases that are extensively used for epidemiological research. NHIRD contains the medical information of all insureds, such as inpatient, outpatient, emergency, and traditional Chinese medicine records. We selected subjects aged ≥ 20 years who recently administered ranibizumab for the ranibizumab cohort. Non-ranibizumab cohort consisted of subjects who did not receive ranibizumab, and the index date was a random date between 2008 and 2018. We excluded subjects with missing sex and age records and those in which the date of primary outcome was before the index date. The two cohorts were matched via 1:1 propensity score matching based on sex, age, index year, hypertension, diabetes mellitus, hyperlipidemia, stroke, coronary artery disease, alcoholism, chronic obstructive pulmonary disease, and age-related macular degeneration, retinal vein occlusion, and diabetic macular edema. Medical confounders were angiotensin I-converting enzyme inhibitors, statins, corticosteroids, VEGF inhibitors including bevacizumab and aflibercept, lithium, amphotericin B, adefovir, NSAIDS, cisplatin, and calcineurin inhibitors. Among 48,248 participants aged ≥ 20 years, 24,136 (50%) received ranibizumab (13,565 male [56.20%] and 10,571 female [43.80%]). Moreover, 24,136 participants who did not receive ranibizumab were matched by age, sex, comorbidities, and medications. Subjects who received ranibizumab exhibited a significantly higher risk of CKD than those who did not receive ranibizumab (adjusted hazard ratio = 1.88, 95% CI = 1.79-1.96). Our findings revealed that exposure to intravitreal ranibizumab is an independent risk factor for CKD. Therefore, physicians and ophthalmologists should make the patients aware of such a correlation to increase patient safety and decrease the CKD burden.
Topics: Humans; Male; Female; Taiwan; Middle Aged; Ranibizumab; Renal Insufficiency, Chronic; Aged; Intravitreal Injections; Angiogenesis Inhibitors; Adult; Risk Factors; Databases, Factual; Cohort Studies; Vascular Endothelial Growth Factor A; Retrospective Studies
PubMed: 38153512
DOI: 10.1007/s00210-023-02910-x -
The Journal of Experimental Biology Jan 2024Elevation in water salinity can threaten the spermatogenesis and fertility of freshwater animals. The role of the renin-angiotensin system (RAS) in regulating...
Elevation in water salinity can threaten the spermatogenesis and fertility of freshwater animals. The role of the renin-angiotensin system (RAS) in regulating spermatogenesis has attracted considerable attention. Our previous study found that red-eared sliders (Trachemys scripta elegans), could survive in 10 PSU water for over 1 year. To understand the chronic impact of salinity on testicular spermatogenesis and underlying mechanisms, male T. s. elegans were subjected to treatment with water of 5 PSU and 10 PSU for a year, and spermatogenesis and regulation of the RAS signal pathway was assessed. Results showed induced inflammation in the testes of T. s. elegans in the 10 PSU group, as evidenced by a decrease in the number of testicular germ cells from 1586 to 943. Compared with the control group, the levels of proinflammatory genes, including TNF-α, IL-12A and IL-6 were elevated 3.1, 0.3, and 1.4 times, respectively, in animals exposed to 10 PSU water. Testicular antiapoptotic processes of T. s. elegans might involve the vasoactive peptide angiotensin-(1-7) in the RAS, as its level was significantly increased from 220.2 ng ml-1 in controls to 419.2 ng ml-1 in the 10 PSU group. As expected, specific inhibitor (A-779) for the Ang-(1-7) acceptor effectively prevented the salinity-induced upregulation of genes encoding anti-inflammatory and antiapoptotic factors (TGF-β1, Bcl-6) in the testis of the 10 PSU animals, whereas it promoted the upregulation of proinflammatory and proapoptotic factors (TNF-α, IL-12A, IL-6, Bax and caspase-3). Our data indicated that Ang-(1-7) attenuates the effect of salinity on inflammation and apoptosis of the testis in T. s. elegans. A new perspective to prevent salinity-induced testis dysfunction is provided.
Topics: Animals; Male; Tumor Necrosis Factor-alpha; Interleukin-6; Salt Stress; Turtles; Inflammation; Spermatogenesis; Water; Angiotensin I; Peptide Fragments
PubMed: 38149682
DOI: 10.1242/jeb.246742 -
International Journal of Molecular... Dec 2023Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling...
Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling processes that lead to right-ventricular heart failure and, ultimately, death. Although our understanding of its pathophysiology has advanced and several treatment modalities are currently available for the management of PAH patients, none are curative and the prognosis remains poor. Therefore, further research is required to decipher the molecular mechanisms associated with PAH. Angiotensin-converting enzyme 2 (ACE2) plays an important role through its vasoprotective functions in cardiopulmonary homeostasis, and accumulating preclinical and clinical evidence shows that the upregulation of the ACE2/Angiotensin-(1-7)/MAS1 proto-oncogene, G protein-coupled receptor (Mas 1 receptor) signaling axis is implicated in the pathophysiology of PAH. Herein, we highlight the molecular mechanisms of ACE2 signaling in PAH and discuss its potential as a therapeutic target.
Topics: Humans; Pulmonary Arterial Hypertension; Angiotensin-Converting Enzyme 2; Hypertension, Pulmonary; Peptidyl-Dipeptidase A; Familial Primary Pulmonary Hypertension; Receptors, G-Protein-Coupled; Angiotensin I; Peptide Fragments; Renin-Angiotensin System
PubMed: 38139269
DOI: 10.3390/ijms242417441 -
Royal Society Open Science Dec 2023Two bisoprolol derivatives, -acetyl bisoprolol and -formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation...
Two bisoprolol derivatives, -acetyl bisoprolol and -formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation and formylation reactions. The yields of the reactions were determined to be 32.40% for -acetyl bisoprolol and 20.20% for -formyl bisoprolol. methods such as molecular docking, molecular dynamics simulation and SwissADME prediction were employed to evaluate the potential of these bisoprolol derivatives as antihypertensive drugs. These methods were used to assess the interaction between the bisoprolol derivatives and various receptors associated with hypertension, including human angiotensin I-converting enzyme (PDB ID: 1O8A), renin (PDB ID: 2V0Z), beta-1 adrenergic receptors (PDB ID: 4BVN, 7BVQ), voltage-dependent L-type calcium channel subunit alpha-1S (PDB ID: 6JP5) and mineralocorticoid receptor (PDB ID: 6L88). Our results demonstrated the highest binding energy when bisoprolol and its derivatives bound to 4BVN, with binding energy values of 6.74 kcal mol, 7.03 kcal mol and 7.63 kcal mol for bisoprolol, -acetyl bisoprolol and -formyl bisoprolol, respectively. The stability of these complexes was confirmed by molecular dynamics simulations, with a root-mean-square deviation value of approximately 2. Furthermore, the SwissADME results indicated that both derivatives exhibited similar properties to the reference drug bisoprolol.
PubMed: 38126063
DOI: 10.1098/rsos.231112 -
Nanoscale Advances Dec 2023This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the...
This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the formation of the enzyme nanocomposite. The immediate application of this work is related to ACE-2 as a mechanism of SARS-CoV-2 entry into cells. Moreover, ACE-2 enzyme regulation is a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. Thus, inhibition of ACE-2 with nanocomposite therapy, may have pharmacologic application with regard to infectious and non-infectious diseases. Synthesized copper nanocomposites described here alone with a commercially available compound, were tested for their potential to inhibit hACE-2 activities. Following wet chemical synthesis, Cu/CuO nanoparticles and graphene-copper (GO-Cu) complexes were synthesized and characterized for their chemical integrity. Cu/CuO formed well-dispersed clusters of 390 ± 100 nm, that when complexed with the hACE-2 enzyme exhibited larger clusters of 506 ± 56 nm. The formation of the Cu/CuO and hACE-2 enzyme complex was monitored by analyzing the zeta potential, which reflected the surface charge distribution of the complex. A negatively charged Cu/CuO nanocomposite nearly becomes neutral when complexed with hACE-2 further assuring the complex formation. Formation of this complex and its inactivation of hACE-2 was evaluated using a standardized protocal for enzymatic activity. Similarly, carboxylate-functionalized graphene was complexed with copper, and its inhibitory effect was studied. Each step in the GO-Cu composite formation was monitored by characterizing its surface electrical properties, resulting in a decrease in its zeta potential and conductivity when complexed with copper. The interaction of the nanocomposites with hACE-2 was confirmed by 2D-FDS and gel electrophoresis analysis. GO-Cu was a rapid and efficacious inhibitor compared to Cu-CuO, especially at lower concentrations (2 μg ml). Considering the environmental friendliness of copper and graphene and their use in industries as surface coating materials, we anticipate that use of these composites once proven effective, may have future antimicrobial application. Utility of nanocomposites as antimicrobials, either as a surface antimicrobial or as an therapeutic, could be invisioned for use against current unknown and/or emergent pathogens.
PubMed: 38125590
DOI: 10.1039/d3na00468f