The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study.

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

Two Novel Angiotensin-Converting Enzyme (ACE) Inhibitory and ACE2 Upregulating Peptides from the Hydrolysate of Pumpkin (Cucurbita moschata) Seed Meal.

Pumpkin (Cucurbita moschata) seed meal (PSM), the major byproduct of pumpkin seed oil industry, was used to prepare angiotensin-converting enzyme (ACE) inhibitory and angiotensin-converting enzyme 2 (ACE2) upregulating peptides. These peptides were isolated and purified from the PSM hydrolysate prepared using Neutrase 5.0 BG by ultrafiltration, Sephadex G-15 column chromatography, and reversed-phase high-performance liquid chromatography. Two peptides with significant ACE inhibition activity were identified as SNHANQLDFHP and PVQVLASAYR with IC50 values of 172.07 and 90.69 µM, respectively. The C-terminal tripeptides of the two peptides contained Pro, Phe, and Tyr, respectively, and PVQVLASAYR also had Val in its N-terminal tripeptide, which was a favorable structure for ACE inhibition. Molecular docking results declared that the two peptides could interact with ACE through hydrogen bonds and hydrophobic interactions. Furthermore, the two peptides performed protective function on EA.hy926 cells by decreasing the secretion of endothelin-1, increasing the release of nitric oxide, and regulating the ACE2 activity. In vitro simulated gastrointestinal digestion showed the two peptides exhibited good stability against gastrointestinal enzyme digestion. In conclusion, PSM is a promising material for preparing antihypertensive peptides.

Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

Protein Hydrolysis as a Way to Valorise Squid-Processing Byproducts: Obtaining and Identification of ACE, DPP-IV and PEP Inhibitory Peptides.

The industrial processing of Argentine shortfin squid to obtain rings generates a significant amount of protein-rich waste, including the skin, which is rich in collagen and attached myofibrillar proteins. This waste is generally discarded. In this study, skin was used as a source of proteins that were hydrolysed using Trypsin, Esperase® or Alcalase®, which released peptides with antioxidant potential and, in particular, antihypertensive (ACE inhibition), hypoglycemic (DPP-IV inhibition) and/or nootropic (PEP inhibition) potential. Among the three enzymes tested, Esperase® and Alcalase produced hydrolysates with potent ACE-, DPP-IV- and PEP-inhibiting properties. These hydrolysates underwent chromatography fractionation, and the composition of the most bioactive fractions was analysed using HPLC-MS-MS. The fractions with the highest bioactivity exhibited very low IC50 values (16 and 66 µg/mL for ACE inhibition, 97 µg/mL for DPP-IV inhibition and 55 µg/mL for PEP inhibition) and were mainly derived from the hydrolysate obtained using Esperase®. The presence of Leu at the C-terminal appeared to be crucial for the ACE inhibitory activity of these fractions. The DPP-IV inhibitory activity of peptides seemed to be determined by the presence of Pro or Ala in the second position from the N-terminus, and Gly and/or Pro in the last C-terminal positions. Similarly, the presence of Pro in the peptides present in the best PEP inhibitory fraction seemed to be important in the inhibitory effect. These results demonstrate that the skin of the Argentine shortfin squid is a valuable source of bioactive peptides, suitable for incorporation into human nutrition as nutraceuticals and food supplements.

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Production of Antioxidant, Angiotensin-Converting Enzyme Inhibitory and Osteogenic Gelatin Hydrolysate from Labeo rohita Swim Bladder.

Optimization of antioxidants and angiotensin-converting enzyme (ACE) inhibitory potential gelatin hydrolysate production from Labeo rohita (rohu) swim bladder (SBGH) by alcalase using central composite design (CCD) of response surface methodology (RSM) was investigated. The maximum degree of hydrolysis (DH), 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), total antioxidants (TAO), and ACE inhibitory activity were achieved at 0.1:1.0 (w/w) enzyme to substrate ratio, 61 °C hydrolysis temperature, and 94-min hydrolysis time. The resulting SBGH obtained at 19.92% DH exhibited the DPPH (24.28 µM TE/mg protein), ABTS (34.47 µM TE/mg protein), TAO (12.01 µg AAE/mg protein), and ACE inhibitory (4.91 µg/mg protein) activity. Furthermore, SBGH at 100 µg/ml displayed osteogenic property without any toxic effects on MC3T3-E1 cells. Besides, the protein content of rohu swim bladder gelatin (SBG) and SBGH was 93.68% and 94.98%, respectively. Both SBG and SBGH were rich in glycine, proline, glutamic acid, alanine, arginine, and hydroxyproline amino acids. Therefore, SBGH could be an effective nutraceutical in functional food development.

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Pressure control and treatment interact in the deterioration of incidental visuospatial memory in hypertensive patients.

BACKGROUND: Systemic hypertension (SH) is the main risk factor to cognitive deterioration, whereas visuospatial memory is more vulnerable to ageing. Some antihypertensive agents have a neuroprotector effect, however, such effects could be masked by comorbidities and/or the lack of effective control on the arterial pressure of patients. OBJECTIVE: To assess this, the evaluation of incidental visuospatial memory of SH patients and the relation to the treatment received and the effective control of pressure were made. METHOD: 80 patients (46 woman) were included grouped by the received medication: angiotensin 2 receptor blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI). A multiple correlation analysis between visuospatial scores and clinical variables was made; also, a mixed model analysis (fixed factors: treatment, pressure control, diabetes comorbidity; aleatory factors: age, schooling, months from SH diagnoses). RESULTS: Half of the patients had a controlled pressure, from them the higher proportion received ARB, and a minor number of patients received ACEI. The normotensive patients receiving ACEI were inefficient whereas the hypertensive patients were more efficient. The systolic pressure was negatively related with the visuospatial scores in spite of no correlations occurred with MoCA and Raven tests. CONCLUSIONS: The visuospatial incidental/intentional scores were negatively correlated with systolic pressure. The efficiency in the visuospatial ability depends on the interaction of treatment and effective control of blood pressure. The interaction between treatment and effective pressure control must be taken in count when cognitive deterioration is studied.

ANTECEDENTES: La hipertensión arterial sistémica (HAS) es el principal factor de riesgo para el deterioro cognitivo; por otro lado, la memoria visuoespacial es más vulnerable al envejecimiento. Algunos fármacos antihipertensivos tienen un efecto neuroprotector, pero tal efecto puede enmascararse o bien no manifestarse por comorbilidad o por falta de control efectivo de la presión arterial. OBJETIVO: Evaluar las alteraciones en la memoria visuoespacial incidental de pacientes con HAS en relación con su tratamiento antihipertensivo y su control de la presión. MÉTODO: Se incluyeron 80 pacientes con HAS (46 mujeres), agrupados por su medicación en bloqueadores de los receptores de la angiotensina II (BRA) o inhibidores de la enzima convertidora de angiotensina (IECA). Se realizó un análisis de correlaciones múltiples para los puntajes obtenidos en la prueba de memoria visuoespacial incidental/intencional y un análisis de modelos mixtos (factores fijos: tratamiento, control de la presión y comorbilidad con diabetes; factores aleatorios: edad, escolaridad, meses desde el diagnóstico de HAS y coeficiente intelectual). RESULTADOS: De los pacientes controlados, la mayoría de los que recibían BRA fueron eficientes y los que recibían IECA fueron deficientes. De los que recibían IECA, los descontrolados hipertensos fueron más eficientes que los normotensos. La memoria visuoespacial se correlacionó negativamente con la presión sistólica a pesar de no haber diferencias en MoCA y Raven. CONCLUSIONES: La eficiencia en la memoria visuoespacial dependió de la interacción del tratamiento y el control de la presión. Ambos factores, tratamiento y control efectivo de la presión, deben considerarse en la evaluación del deterioro cognitivo asociado a la HAS.

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure.

BACKGROUND: The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. OBJECTIVES: Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. METHODS: The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. RESULTS: The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). CONCLUSIONS: In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).

A simple tandem bioassay-guided SCX-RP SPE fractionation for efficient active peptide screening from Inca nut cake protein hydrolysate.

Typically, bioactive peptides were uncovered from complex hydrolysates using sequential bioassay-guided fractionation. To increase the efficiency of bioactive peptide screening, a simple and convenient tandem bioassay-guided fractionation based on solid-phase extraction (SPE) was conducted to screen the angiotensin-I-converting enzyme (ACE) inhibitory peptides from the hydrolysate of Inca nut cake protein (INCP). The so-called SCX-RP SPE system was constructed by assembling SCX (strong cation exchange) and RP (reversed phase) SPE cartridges. Using this tandem SCX-RP SPE, the INCP digested with combined gastrointestinal protease (INCP GP) was fractionated into 30 fractions. The fraction F11 exhibited the highest ACE inhibitory activity among 30 fractions. The ACE IC50 of fraction F11 was calculated to be 6.6 ± 0.5 µg/mL. The ACEI activity of fraction F11 was stronger than the INCP GP hydrolysate (ACE IC50 of 12.7 ± 0.4 µg/mL). The tandem SCX-RP SPE fractionation reduced the number of ACE inhibitory (ACEI) peptide candidates from 127 peptides in the INCP GP hydrolysate to only ten peptides in fraction F11. Subsequently, WALPTQSW (WW-8) and WLPTKSW (WW-7) from fraction F11 were synthesized, and their ACE IC50 was determined to be 4.7 ± 0.1 and 7.9 ± 0.1 µM, respectively. The dipeptidyl peptidase-4 (DPP4) inhibitory and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activities of WALPTQSW (WW-8) were also explored to give IC50 values of 131.7 ± 5.2 and 191.8 ± 7.0 µM, respectively. The molecular docking and inhibition mechanism studies indicated that WW-8 inhibited ACE and DPP4 as competitive and non-competitive inhibitors, respectively. The pre-incubation experiment of WW-8 toward ACE and DPP4 demonstrated that WW-8 was a true-inhibitor type. Additionally, the amount of WW-8 was quantified to be 5.8 ± 0.2 and 35 ± 0.4 µg per milligram hydrolysate and fraction F11, respectively. This study demonstrated tandem bioassay-guided SCX-RP SPE fractionation efficiently screened ACEI peptide derived from INCP GP hydrolysate, adding more value to Inca nut cake (a leftover of the oil industry) as a bioactive peptide precursor.

Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression.

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-ß1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.

Renin-angiotensin-aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial.

INTRODUCTION: Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. MATERIALS AND METHODS: Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3-4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years. Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. RESULTS: 88 patients were included with a mean age of 77.9±6.1 years and a follow up period of 3 years: 40 were randomized to RAAS group and 48 to standard treatment. Ethiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown ethiology. In the RAAS group eGFR slope during follow up was -4.3±1.1ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6±0.4ml/min), p=0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. CONCLUSIONS: In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression. The PROERCAN (PROgresión de Enfermedad Renal Crónica en ANcianos) trial (trial registration: NCT03195023).

To what extent do water reuse treatments reduce antibiotic resistance indicators? A comparison of two full-scale systems.

Water reuse is an essential strategy for reducing water demand from conventional sources, alleviating water stress, and promoting sustainability, but understanding the effectiveness of associated treatment processes as barriers to the spread of antibiotic resistance is an important consideration to protecting human health. We comprehensively evaluated the reduction of antibiotic resistance genes (ARGs) and antibiotic-resistant bacteria (ARB) in two field-operational water reuse systems with distinct treatment trains, one producing water for indirect potable reuse (ozone/biologically-active carbon/granular activated carbon) and the other for non-potable reuse (denitrification-filtration/chlorination) using metagenomic sequencing and culture. Relative abundances of total ARGs/clinically-relevant ARGs and cultured ARB were reduced by several logs during primary and secondary stages of wastewater treatment, but to a lesser extent during the tertiary water reuse treatments. In particular, ozonation tended to enrich multi-drug ARGs. The effect of chlorination was facility-dependent, increasing the relative abundance of ARGs when following biologically-active carbon filters, but generally providing a benefit in reduced bacterial numbers and ecological and human health resistome risk scores. Relative abundances of total ARGs and resistome risk scores were lowest in aquifer samples, although resistant Escherichia coli and Klebsiella pneumoniae were occasionally detected in the monitoring well 3-days downgradient from injection, but not 6-months downgradient. Resistant E. coli and Pseudomonas aeruginosa were occasionally detected in the nonpotable reuse distribution system, along with increased levels of multidrug, sulfonamide, phenicol, and aminoglycoside ARGs. This study illuminates specific vulnerabilities of water reuse systems to persistence, selection, and growth of ARGs and ARB and emphasizes the role of multiple treatment barriers, including aquifers and distribution systems.

Concurrent exercise training potentiates the effects of angiotensin-converting enzyme inhibitor on regulatory systems of blood pressure control in ovariectomized hypertensive rats.

OBJECTIVE: Enalapril has shown satisfactory potential in controlling increased and sustained blood pressure (BP). However, multiple dysregulated mechanisms that interact with each other and are involved in the pathophysiology of arterial hypertension may not be affected, contributing to the remaining cardiovascular risk. Using an exercise training protocol, we investigated whether adding both approaches to arterial hypertension management could promote higher modulation of regulatory mechanisms of BP in postmenopausal rats. METHODS: Spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with enalapril maleate (OSE) and trained treated with enalapril maleate (OTE). Both the pharmacological and exercise training protocols lasted for 8 weeks. The BP was directly recorded. Inflammation and oxidative stress were evaluated in the cardiac tissue. RESULTS: Although BP reduction was similar between OSE and OTE, trained group showed lower vasopressor systems outflow after sympathetic ganglion blocking by hexamethonium (mean BP) (OTE: -53.7 ±â€Š9.86 vs. OS: -75.7 ±â€Š19.2 mmHg). Bradycardic and tachycardic response were increased in OTE group (-1.4 ±â€Š0.4 and -2.6 ±â€Š0.4 vs. OS: -0.6 ±â€Š0.3 and -1.3 ±â€Š0.4 bpm/mmHg, respectively), as well as BP variability. In addition, the combination of approaches induced an increase in interleukin 10, antioxidant defense (catalase and glutathione peroxidase) and nitrite levels compared with the OS group. CONCLUSION: Despite similar BP, the inclusion of exercise training in antihypertensive drug treatment exacerbates the positive adaptations induced by enalapril alone on autonomic, inflammatory and oxidative stress profiles, probably affecting end-organ damage and remaining risk.

Pharmacological inhibition of the ACE/Ang-2/AT1 axis alleviates mechanical ventilation-induced pulmonary fibrosis.

Mechanical ventilation (MV) is an essential therapy for acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. However, it can also induce mechanical ventilation-induced pulmonary fibrosis (MVPF) and the underlying mechanism remains unknown. Based on a mouse model of MVPF, the present study aimed to explore the role of the angiotensin-converting enzyme/angiotensin II/angiotensin type 1 receptor (ACE/Ang-2/AT1R) axis in the process of MVPF. In addition, recombinant angiotensin-converting enzyme 2(rACE2), AT1R inhibitor valsartan, AGTR1-directed shRNA and ACE inhibitor perindopril were applied to verify the effect of inhibiting ACE/Ang-2/AT1R axis in the treatment of MVPF. Our study found MV induced an inflammatory reaction and collagen deposition in mouse lung tissue accompanied by the activation of ACE in lung tissue, increased concentration of Ang-2 in bronchoalveolar lavage fluid (BALF), and upregulation of AT1R in alveolar epithelial cells. The process of pulmonary fibrosis could be alleviated by the application of the ACE inhibitor perindopril, ATIR inhibitor valsartan and AGTR1-directed shRNA. Meanwhile, rACE2 could also alleviate MVPF through the degradation of Ang-2. Our finding indicated the ACE/Ang-2/AT1R axis played an essential role in the pathogenesis of MVPF. Pharmacological inhibition of the ACE/Ang-2/AT1R axis might be a promising strategy for the treatment of MVPF.

The fate of antibiotic resistance genes in wastewater containing microalgae treated by chlorination, ultra-violet, and Fenton reaction.

Antibiotic resistance genes (ARGs) and bacteria (ARBs) in the effluent of wastewater treatment plants (WWTPs) are of utmost importance for the dissemination of ARGs in natural aquatic environments. Therefore, there is an urgent need for effective technologies to eliminate WWTP ARGs/ARBs and mitigate the associated risks posed by the discharged ARG in aquatic environments. To test the effective technology for eliminating ARGs/ARBs, we compared the removal of ARGs and ARBs by three different tertiary treatments, namely ultra-violet (UV) disinfection, chlorination disinfection, and Fenton oxidation. Then, the treated wastewater was co-cultured with Chlorella vulgaris (representative of aquatic biota) to investigate the fate of discharged ARGs into the aquatic environment. The results demonstrated that chlorination (at a chlorine concentration of 15 mg/L) and Fenton (at pH 2.73, with 0.005 mol/L Fe2+ and 0.0025 mol/L H2O2) treatment showed higher efficacy in ARG removal (1.8 - 4.17 logs) than UV treatment (15 min) (1.29 - 3.87 logs). Moreover, chlorine at 15 mg/L and Fenton treatment effectively suppressed ARB regeneration while UV treatment for 15 min could not. Regardless of treatments tested in this study, the input of treated wastewater to the Chlorella system increased the number of ARGs and mobile genetic elements (MGEs), indicating the potential risk of ARG dissemination associated with WWTP discharge. Among the wastewater-Chlorella co-culture systems, chlorination resulted in less of an increase in the number of ARGs and MGEs compared to Fenton and UV treatment. When comparing the wastewater systems to the co-culture systems, it was observed that Chlorella vulgaris reduced the number of ARGs and MGEs in chlorination and UV-treated wastewater; however, Chlorella vulgaris promoted ARG survival in Fenton-treated water, suggesting that aquatic microalgae might act as a barrier to ARG dissemination. Overall, chlorination treatment not only effectively removes ARGs and inhibits ARB regeneration but also shows a lower risk of ARG dissemination. Therefore, chlorination is recommended for practical application in controlling the spread of discharged ARGs from WWTP effluent in natural aquatic environments.

Molecular level removal of antibiotic resistant bacteria and genes: A review of interfacial chemical in advanced oxidation processes.

As a kind of novel and persistent environmental pollutants, antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) have been frequently detected in different aquatic environment, posing potential risks to public health and ecosystems, resulting in a biosecurity issue that cannot be ignored. Therefore, in order to control the spread of antibiotic resistance in the environment, advanced oxidation technology (such as Fenton-like, photocatalysis, electrocatalysis) has become an effective weapon for inactivating and eliminating ARB and ARGs. However, in the process of advanced oxidation technology, studying and regulating catalytic active sites at the molecular level and studying the adsorption and surface oxidation reactions between catalysts and ARGs can achieve in-depth exploration of the mechanism of ARGs removal. This review systematically reveals the catalytic sites and related mechanisms of catalytic antagonistic genes in different advanced oxidation processes (AOPs) systems. We also summarize the removal mechanism of ARGs and how to reduce the spread of ARGs in the environment through combining a variety of characterization methods. Importantly, the potential of various catalysts for removing ARGs in practical applications has also been recognized, providing a promising approach for the deep purification of wastewater treatment plants.