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In an effort to discover new agents with good fungicidal activities against CDM (cucumber downy mildew), a series of tetrazole derivatives containing phenyloxadiazole moieties were designed and synthesized. The EC 50 values for fungicidal activities against CDM were determined. Bioassay results indicated that most synthesized compounds exhibited potential in vivo fungicidal activity against CDM. A CoMFA (comparative molecular field analysis) model based on the bioactivity was developed to identify some primary structural quality for the efficiency. The values of q 2 and r 2 for the established model were 0.791 and 0.982 respectively, which reliability and predict abilities were verified. Three analogues (q3, q4, q5) were designed and synthesized based on the model. All these compounds exhibited significant fungicidal activity on CDM with the EC 50 of 1.43, 1.52, 1.77 mg·L -1 . This work could provide a useful instruction for the further structure optimization., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic cerebral ischemia with a notable long-term cessation of blood supply to the brain tissues leads to sensorimotor defects and short- and long-term memory problems. Neuroprotective agents are used in an attempt to save ischemic neurons from necrosis and apoptosis, such as the antioxidant agent Eucalyptus . Numerous studies have demonstrated the involvement of the renin-angiotensin system in the initiation and progression of cardiovascular and neurodegenerative diseases. Candesartan is a drug that acts as an angiotensin II receptor 1 blocker. We established a rat model exhibiting sensorimotor and cognitive impairments due to chronic cerebral ischemia induced by the ligation of the right common carotid artery. Wistar male rats were randomly divided into five groups: Sham group, Untreated Ligated group, Ischemic group treated with Eucalyptus (500 mg/kg), Ischemic group treated with Candesartan (0.5 mg/kg), and Ischemic group treated with a combination of Eucalyptus and Candesartan. To evaluate the sensorimotor disorders, we performed the beam balance test, the beam walking test, and the modified sticky test. Moreover, the object recognition test and the Morris water maze test were performed to assess the memory disorders of the rats. The infarct rat brain regions were subsequently stained using the triphenyltetrazolium chloride staining technique. The rats in the Sham group had normal sensorimotor and cognitive functions without the appearance of microscopic ischemic brain lesions. In parallel, the untreated Ischemic group showed severe impaired neurological functions with the presence of considerable brain infarctions. The treatment of the Ischemic group with a combination of both Eucalyptus and Candesartan was more efficient in improving the sensorimotor and cognitive deficits ( p < 0.001) than the treatment with Eucalyptus or Candesartan alone ( p < 0.05), by the comparison to the non-treated Ischemic group. Our study shows that the combination of Eucalyptus and Candesartan could decrease ischemic brain injury and improve neurological outcomes.

We examined the effects of a fixed-dose single-pill combination of cilnidipine (10 mg), an L-/N-type calcium channel blocker, and valsartan (80 mg) (SPC of Cil/Val) on the day-by-day variability of morning home systolic blood pressure (MHSBP) in 616 patients with treated hypertension for 12 months as a sub-analysis of the HOPE-Combi survey, multicentral, post-marketing, and prospective observational survey. The SPC of Cil/Val was administrated once a day in the morning. The SPC of Cil/Val decreased the standard deviation (SD, from 6.3 ± 4.8 to 5.1 ± 3.8 mmHg, p < .01), coefficient of variation (from 4.3 ± 3.2 to 3.8 ± 2.9%, p < .05), average real variability (ARV, from 7.9 ± 6.6 to 6.3 ± 5.1 mmHg, p < .01), and the difference between maximum and minimum (MMD, from 11.9 ± 9.2 to 9.7 ± 7.2 mmHg, p < .01) of MHSBP. The variability of MHSBP increased with age; however, this was not increased in patients ≥70 years at the baseline. In elderly patients (≥70 years, N = 283), the SPC of Cil/Val decreased the SD (from 6.9 ± 5.6 to 5.6 ± 4.4 mmHg, p < .01), ARV (from 8.6 ± 7.7 to 6.9 ± 5.7 mmHg, p < .05), and MMD (from 13.2 ± 10.7 to 10.7 ± 8.3 mmHg, p < .01) of MHSBP at 12 months; the reduction in these MHSBP variability parameters was comparable to that in adults <70 years. These results suggest that the SPC of Cil/Val is effective in reducing day-by-day variability of MHSBP in elderly patients., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Introduction : Despite the introduction of numerous new antiseizure medications (ASMs) still about one-third of epilepsies remain drug-resistant. Therefore, new compounds with advanced efficacy are urgently needed. Cenobamate (CNB) is a new ASM that has been recently introduced in the United States for the treatment of adults with focal-onset seizures. The approval in Europe is under way. Areas covered : This review covers the pharmacological profile of CNB, the proof-of-concept trial, the two double-blind, placebo-controlled phase 2 trials investigating adjunct CNB in adults with focal-onset seizures, one open-label safety trial, and a variety of published abstract material that provided additional post hoc data. Expert opinion : In two placebo-controlled randomized multicenter phase 2 trials adjunct CNB showed unusually high efficacy with rates of seizure-free people with epilepsy (PWE) partially beyond 20%. However, during the clinical program cases of drug-related reactions with eosinophilia and systemic symptoms (DRESS syndrome) occurred. Therefore, an open-label safety study was performed in more than 1300 PWE with particularly slower titration schedules which did not add more cases with similar reactions. Taking into consideration the promising efficacy and the safety experience from the open-label trial, CNB applied according to the meanwhile recommended titration strategy, might offer a new prospect.

Aims: Pulmonary hypertension (PH) is a fatal disease identified by progressive elevated pulmonary arterial pressure, which neurohormonal activation is a notable contributor to its development. Sacubitril/valsartan is a complex of sacubitril [via enhancing the natriuretic peptide (NP) system] and valsartan [via blocking the renin-angiotensin-aldosterone system (RAAS)]. Regulation of the two neurohormonal system had been shown to attenuate PH. This study was to explore the role of sacubitril/valsartan in both monocrotaline (MCT)-induced and hypoxia-induced rat models and the underlying mechanism., Main Methods: The rats were treated with MCT or hypoxic environment for 14 days, after that sacubitril/valsartan were given for another 14 days. Hemodynamic measurements and histological assessments were performed. The expression of NPs was measured using RT-PCR and ELISA, while the protein level of natriuretic peptide receptors (NPRs) and AT1 receptor were detected by western blot, the concentrations of cGMP, IL-1β, IL-6, TNF-α and TGF-β1 were tested by ELISA., Key Findings: We found that sacubitril/valsartan significantly improved the hemodynamic and histological data of two PH models. Sacubitril/valsartan suppressed the protein expression of AT1 receptor (P < 0.05). The intervention increased the expression of ANP and CNP (P< 0.05) and therefore upregulated the protein expression of NPRs (P < 0.05), raised the concentration of cGMP (P < 0.05). In addition, the treatment reduced the concentration of IL-1β, IL-6 and TNF-α (P < 0.05) but have no effects on TGF-β1., Significance: Sacubitril/valsartan alleviated PH in MCT-induced and hypoxia-induced rat models by inhibiting the activated RAAS, promoting ANP/NPR-A/cGMP and CNP/NPR-B/cGMP pathway, restoring the NPR-C signaling and the anti-inflammatory effects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX)., Methods: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied., Results: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF., Conclusion: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), is reported to play a cardioprotective role after acute myocardial infarction (AMI). Angiotensin-converting enzyme inhibitors(ACEIs) have similar roles. However, it is unclear whether the combination of the two drugs has a better protective effect. The purpose of this study was to investigate the effect of this combination therapy after AMI., Methods: Male C57BL/6 J mice subjected to ligation of left anterior descending artery were treated for 4 weeks with LCZ696, ACEI(benazepril), or both(combination therapy) after induction of MI. Cardiac function, hemodynamics, and inflammatory factors were evaluated at 1 st day, 14th day, and 28th day. Heart weight and myocardial fibrosis were measured at the end of the experiment., Results: Blood pressure was lower in all treatment groups than in the control group. The combination therapy group had the strongest antihypertensive effect. Compared with LCZ696 or benazepril, treatment with combination therapy increased ejection fraction, fractional shortening, and cardiac output and decreased N-terminal pro-B-type natriuretic peptide(NT-proBNP). The ratios of heart weight to body weight in all treatment groups were less than that in the control group. Compared with the control and LCZ696 group, the fibrotic area in the combination therapy group was suppressed and had a lower level of TGF-β1 in the left ventricle. The plasma concentration of bradykinin and renin in the combination therapy group were highest among groups at 14th and 28th day., Conclusions: LCZ696 in combination with benazepril showed better positive effects in modulating heart failure and myocardial fibrosis after acute AMI in mice and affect some inflammatory markers., (Copyright © 2020. Published by Elsevier Masson SAS.)

Introduction: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial., Methods: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR)., Results: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups., Conclusion: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds ( 4a - g ) displayed good antiplasmodium activities (IC 50 = 0.20-0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (<20 µM). Compound 4e was 2-fold more active than primaquine and was also the most active (IC 50 = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7.

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K 2P 2.1 (TREK-1) K + channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca 2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca 2+ channels (Ca V ) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa 2+ concentrations. In addition, CCL-2 secretion was decreased after L-type Ca V inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or β-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First,  the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.

Excitation-contraction coupling from the integration of action potential duration (APD) and muscle contractility plays an important role in arrhythmogenesis. We aimed to determine whether distinctive excitation-contraction coupling contributes to the genesis of ventricular tachycardias (VTs). Action potential (AP) and mechanical activity were simultaneously recorded under electrical pacing (cycle lengths from 1000 to 100 ms) in the tissue model created from isolated rabbit right ventricular outflow tracts treated with NS 5806 (10 μM, transient outward potassium current enhancer), pinacidil (2 μM, ATP-sensitive potassium channel opener), and pilsicainide (5 μM, sodium channel blocker). There were 15 (9.9%) inducible VT episodes (group 1) and 136 (90.1%) non-inducible VT episodes (group 2) in our tissue model. Group 1 had greater post-pacing increases of the first occurrence of AP at 90% repolarization (ΔAPD 90 , p < 0.001) and contractility (ΔContractility, p = 0.003) compared with group 2. Triggered VT episodes were common (72.7%) in cases with a ΔAPD 90 > 15% and a ΔContractility > 270%, but were undetectable in those with a ΔAPD 90 < 15% and a ΔContractility < 270%. In those with pacing-induced VTs, KB-R7943 (10 μM, a Na + -Ca 2+ exchanger inhibitor, NCX inhibitor) significantly reduced the occurrence of VTs from 100.0 to 20.0% (15/15 to 3/15 episodes, p < 0.001). Concurrent increases in both post-pacing APD and contractility resulted in the occurrence of ventricular arrhythmias. NCX inhibition may be a potential therapeutic strategy for ventricular arrhythmias.

Background: Sepsis induces pulmonary P2X 7 receptor (P2X 7 R) expression and P2X 7 R-knockout reduced lung inflammation in mice. The present study investigated the expression of circular RNA (circRNA) and mRNA in sepsis-induced acute lung injury (ALI) treated with a P2X 7 R antagonist., Methods: Sepsis was induced by tracheal administration of lipopolysaccharide (LPS), and the mice were then divided into two groups: without [sepsis + dimethyl sulfoxide (DMSO)] or with P2X 7 R antagonist treatment (sepsis + P2X 7 A). Sham mice were administrated sterile normal saline. Serum levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, pathological changes, cell apoptosis and P2X 7 R expression in lung were assessed, followed by RNA sequencing (RNA-seq) and bioinformatics analyses. A quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to validate circRNAs and mRNAs., Results: Compared to the sham group, LPS-induced sepsis produced obvious pathological changes in lung tissue, as well as increased apoptotic lung cells, serum TNF-α and IL-1β levels, and P2X 7 R expression; P2X 7 R antagonism significantly ameliorated these changes. RNA-seq identified many dysregulated circRNAs and mRNAs during sepsis, whereas this changed with P2X 7 R antagonism. RT-qPCR confirmed that Mus musculus (mmu)&#95;circ&#95;0001679, mmu&#95;circ&#95;0001212, phospholamban (Pln), cadherin-2 (Cdh2) and nitrogen permease regulator 3-like (Nprl3) expression were significantly increased in the sepsis + DMSO group compared to that in the sham group but were decreased in the sepsis + P2X 7 A group compared to that in the sepsis + DMSO group. The circRNA-microRNA-mRNA coexpression network indicated that mmu&#95;circ&#95;0001679 may regulate Nprl3 and that mmu&#95;circ&#95;0001212 may similarly regulate Pln, Cdh2 and Nprl3 as a competing endogenous RNA., Conclusions: P2X 7 R antagonism attenuates sepsis-induced ALI by inhibiting dysregulated expression of circRNA (circ&#95;0001679, circ&#95;0001212) and mRNA (Pln, Cdh2 and Nprl3)., (© 2020 John Wiley & Sons, Ltd.)

Background: Withaferin A is a functional ingredient of a traditional medicinal plant, Withania somnifera, which has been broadly used in India for protecting against chronic diseases. This bioactive steroidal lactone possesses multiple functions such as anti-oxidation, anti-inflammation, and immunomodulation. Chronic kidney disease (CKD) is one of the major health problems worldwide with the high complication, morbidity, and mortality rates. The detailed effects and underlying mechanisms of withaferin A on CKD progression still remain to be clarified., Purpose: We aimed to investigate whether withaferin A treatment ameliorates the development of renal fibrosis and its related mechanisms in a CKD mouse model., Methods: A mouse model of unilateral ureteral obstruction (UUO) was used to mimic the progression of CKD. Male adult C57BL/6J mice were orally administered with 3 mg/kg/day withaferin A for 14 consecutive days after UUO surgery. Candesartan (5 mg/kg/day) was used as a positive control., Results: Both Withaferin A and candesartan treatments significantly ameliorated the histopathological changes and collagen deposition in the UUO kidneys. Withaferin A could significantly reverse the increases in the protein levels of pro-fibrotic factors (fibronectin, transforming growth factor-β, and α-smooth muscle actin), inflammatory signaling molecules (phosphorylated nuclear factor-κB-p65, interleukin-1β, and cyclooxygenase-2), and cleaved caspase-3, apoptosis, and infiltration of neutrophils in the UUO kidneys. The protein levels of endoplasmic reticulum (ER) stress-associated molecules (GRP78, GRP94, ATF4, CHOP, phosphorylated eIF2α, and cleaved caspase 12) were increased in the kidneys of UUO mice, which could be significantly reversed by withaferin A treatment., Conclusion: Withaferin A protects against the CKD progression that is, at least in part, associated with the moderation of ER stress-related apoptosis, inflammation, and fibrosis in the kidneys of CKD. Withaferin A may serve as a potential therapeutic agent for the development of CKD., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Angiotensin (1-7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1-7) (angiotensin [1-7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1-7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1-7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1-7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1-7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1-7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1-7) increased MasR expression and reduced M/L in Ang II (angiotensin II)-infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

During the last decades, much attention has been focused on SNEDDS approach to resolve concerns of BCS II class drugs with accentuation on upgrading the solubility and bioavailability. The present hypothesis confirms the theory that SNEDDS can reduce the impact of food on Candesartan solubilization, thereby offering the potential for improved oral delivery without co-administration with meals. The present studies describe quality-by-design-based development and characterization of Candesartan loaded SNEDDS for improving its pharmacodynamic potential. D-optimal mixture design was used for systematic optimization of SNEDDS, which showed globule size of 13.91 nm, more rapid drug release rate of >90% in 30 min and 16 s for self-emulsification. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated up to 1.99- and 1.10-fold enhancement in dissolution rate from SNEDDS over pure drug and marketed tablet. In vivo pharmacodynamic investigation also showed superior antihypertensive potential of SNEDDS in normalizing serum lipid levels as compared to pure drug and marketed tablet that was executed on male Wistar rats. Overall, this paper reports successful systematic development of candesartan-loaded SNEDDS with distinctly improved biopharmaceutical performance. This research work interpreted a major role of SNEDDS for enhancing the rate of dissolution and bioavailability of poorly water soluble drugs.

What Is Known and Objective: There is much controversy over how angiotensin II receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) affect blood uric acid levels. Though ARB is not used to lorcwer the uric acid concentration in the blood, losartan, one of the ARB series, is known to reduce the uric acid concentration in the blood and is a preferred drug for hypertensive patients with gout. However, there is no clear conclusive consideration which ARB should be selected for the patients who have simply increased uric acid concentration, other than gout patients. This research aims to compare the variations of the uric acid concentration in the blood in accordance with the prescription of ACEI or ARB targeting patients who were not diagnosed with gout., Methods: This research was conducted on the patients who were, for the first time, prescribed ACEI or ARB for a total of 7 years from January 2009 to December 2015. This study has extracted the uric acid values after between 60 days and 120 days (average 90 days, defined as Visit 1) on the basis of the first prescription date of ACEI or ARB., Results and Discussion: In this study, ACEI was 17.0% of usage (3787/22 293 patients) and ARB was 83.0% (18 506/22 293 patients). Unlike ACEI (5.91 ± 0.03 vs 5.86 ± 0.03 mg/dL, P = .059), ARB showed a statistically significant decrease after 3 months (5.71 ± 0.01 vs 5.69 ± 0.01 mg/dL, P = .023). In the case of irbesartan (n = 1530, 6.13 ± 0.06 mg/dL vs 5.89 ± 0.05 mg/dL, P < .001) and olmesartan (n = 2719, 5.70 ± 0.04 mg/dL vs 5.63 ± 0.03 mg/dL, P = .008), the decrease in the uric acid after 3 months was revealed as statistically significant. In elderly aged over 60 years, only irbesartan (n = 855, 5.75 ± 0.07 mg/dL vs 5.59 ± 0.07 mg/dL, P = .006) showed a significant decrease in the uric. When the eGFR was less than 60 mL/min/1.73 m 2 , both ACEI (n = 1108, 6.95 ± 0.07 mg/dL vs 6.73 ± 0.07 mg/dL, P = .001) and ARB (n = 5280, 6.88 ± 0.03 vs 6.60 mg/dL ± 0.03 mg/dL, P < .001) showed a significant decrease in the uric acid., What Is New and Conclusion: Although all types of ACEIs and ARBs are being prescribed with similar purposes, ARB (or ACEI) medication does not have a class effect and has varying effects on uric acid levels. The decreases in uric acid levels were relatively small. ARBs seem to be more advantageous than ACEIs for hyperuricaemia patients without gout who are aiming to maintain uric acid decrease levels. Furthermore, irbesartan can be a good substitute for losartan in view of the fact that at least the uric acid level is not increased., (© 2020 John Wiley & Sons Ltd.)

Background: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin., Methods: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF., Results: Acacetin (5-10 μM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF., Conclusions: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS., Competing Interests: The authors have declared that no competing interests exist.

The overall prognosis for pancreatic cancer remains dismal and potent chemotherapeutic agents that selectively target this cancer are critically needed. Elevated expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxicity remains elusive. Here, we show that KP372-1 sensitizes NQO1-expressing pancreatic cancer cells and spares immortalized normal pancreatic duct cells, hTERT-HPNE. Notably, we found that KP372-1 is ~ 10- to 20-fold more potent than β-lapachone, another NQO1 substrate, against pancreatic cancer cells. Mechanistically, our data strongly suggest that reactive oxygen species produced by NQO1-dependent redox cycling of KP372-1 cause robust DNA damage, including DNA breaks. Furthermore, we found that KP372-1-induced DNA damage hyperactivates the central DNA damage sensor protein poly(ADP-ribose) polymerase 1 (PARP1) and activates caspase-3 to initiate cell death. Our data also show that the combination of KP372-1 with PARP inhibition creates enhanced cytotoxicity in pancreatic cancer cells. Collectively, our study provides mechanistic insights into the cytotoxicity instigated by KP372-1 and lays an essential foundation to establish it as a promising chemotherapeutic agent against cancer.

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by 1 H NMR, 13 C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC 50 values (0.78-3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To search for effective and selective COX-2 inhibitors, four novel series of tetrazole derivatives were designed based on bioisosteric replacement of SO 2 NH 2 in celecoxib with tetrazole ring incorporating different central moieties as chalcone (2a-f), isoxazole (3a-c) or pyrazole (4a-c & 5a-c). Target tetrazoles were synthesized and their structures were confirmed by spectroscopic techniques and elemental analyses. All target compounds were more selective for COX-2 isozyme than COX-1 when compared to standard drugs indomethacin and celecoxib. Compounds 3b, 3c, 4b, 4c, 5b and 5c exhibited potent in vitro COX-2 inhibitory activity (IC 50  = 0.039-0.065 μM). Trimethoxy derivatives 3c, 4c and 5c acquired superior COX-2 selectivity index values (SI = 297.67-317.95) and were 1.1 fold higher than celecoxib (SI = 282.22). The most active six compounds were evaluated for their in vivo anti-inflammatory activity and serum levels of PGE 2 , TNF-α and IL-6 in addition to their ulcerogenic liability and histopathological profile. At a dose of 50 mg/Kg, compounds 3c and 5c showed better anti-inflammatory activity (% edema inhibition = 29.209-42.643) than celecoxib (% edema inhibition = 28.694-40.114) at different time intervals and were less ulcerogenic (UI = 0.123 and 0.11 in sequent) than celecoxib (UI = 0.167). Also, they displayed potent inhibitory effect on the production of PGE 2 (% inhibition = 81.042 and 82.724 in sequent) greater than celecoxib (% inhibition = 79.666). Compound 5c decreased rat serum concentrations of both TNF-α (% inhibition = 55.349) and IL-6 (% inhibition = 61.561) in a comparable or better activity to celecoxib as reference drug. Finally, docking poses of the most active compounds showed strong binding interactions and effective overall docking energy scores explaining their remarkable COX-2 inhibitory activity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism., Methods: Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg . kg -1. d -1 olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ., Results: After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect., Conclusion: Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway., (Copyright © 2020. Published by Elsevier Inc.)

Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD 50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals., (© Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

Background/aims: Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established a model of arrhythmia-induced heart failure (HF) in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation by using an angiotensin II type 1 receptor blocker, fimasartan, through the assessment of cellular and physiologic responses, morbidity, and mortality., Methods: HF was induced in zebrafish larvae by exposure to 20 μM terfenadine. Morphologic, physiologic, and functional parameters were assessed in the presence or absence of fimasartan treatment., Results: Zebrafish exposed to terfenadine showed marked dilatation of the ventricle and reduced systolic function. Treatment with terfenadine was associated with 10-fold higher expression of atrial natriuretic peptide (p < 0.001 vs. vehicle), increased p53 mRNA expression, and chromatin fragmentation in the TUNEL assay, all of which were significantly reduced by fimasartan treatment. Moreover, fimasartan improved fractional shortening (terfenadine + fimasartan 16.9% ± 3.1% vs. terfenadine + vehicle 11.4% ± 5.6%, p < 0.05) and blood flow (terfenadine + fimasartan 479.1 ± 124.1 nL/sec vs. terfenadine + vehicle 273.0 ± 109.0 nL/sec, p < 0.05). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine + vehicle 96.0%, p < 0.001)., Conclusion: Fimasartan effectively protected against the progression of HF in zebrafish by improving hemodynamic indices, which improved survival. A reduction in apoptotic cell death and an improvement in hemodynamics may be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in the treatment of HF.

Importance: Sacubitril-valsartan use reduces mortality and hospitalizations compared with enalapril among patients with chronic heart failure with reduced ejection fraction (HFrEF); however, the cost-effectiveness of these treatments when initiated during hospitalization for HF is unknown., Objective: To estimate the cost-effectiveness of inpatient initiation of sacubitril-valsartan vs enalapril compared with no initiation or posthospitalization initiation of sacubitril-valsartan among stabilized patients with HFrEF., Design, Setting, and Participants: This economic evaluation included data on US patients with HFrEF who were eligible for sacubitril-valsartan treatment from December 8, 2009, to May 15, 2018., Main Outcomes and Measures: A 5-state Markov model with all-cause mortality, HF, and non-HF hospitalization probabilities was used. Quality of life was estimated using Euro-QoL EQ-5D scores. Hospitalization, long-term care, and medication costs for sacubitril-valsartan and enalapril were modeled with a discount rate of 3%. The base-case analysis included a lifetime horizon from a health care and societal perspective., Results: Modeled patients were a mean (SD) age of 63.8 (11.5) years. Inpatient treatment with sacubitril-valsartan ($5628 per year) was associated with 62 fewer HF-related admissions per 1000 patients compared with outpatient initiation or 116 fewer HF-related admissions compared with continuation of enalapril treatment. From a health care system perspective, initiation of sacubitril-valsartan during hospitalization saved $452 per year compared with continuing enalapril and $811 per year compared with initiation at 2 months after hospitalization and was associated with an incremental cost-effectiveness ratio of $21 532 per quality-adjusted life-year compared with continued enalapril treatment over a lifetime. From a societal perspective, inpatient initiation was estimated to save $460 per year per patient compared with no initiation of sacubitril-valsartan and $813 per year per patient compared with initiation after hospitalization. In a budget analysis, inpatient initiation of sacubitril-valsartan was estimated to save up to $449 per person for 1 year or $2550 per person over 5 years compared with continuation of enalapril., Conclusions and Relevance: The findings suggest that, for patients with HFrEF, initiation of sacubitril-valsartan during hospitalization may be associated with reduced hospitalizations, increased quality-adjusted life expectancy, and cost savings compared with no initiation or initiation after hospitalization.

β-Lactam antibiotics such as ceftriaxone, are potent stimulators of the expression of l-glutamate transporter GLT-1 and may exert neuroprotective effects when chronically used in rats and mice. In this study, we used two animal models to test the neurological effect of subchronic treatment with ceftriaxone: experimental acute glaucoma in Wistar rats and induction of acute seizures with pentylenetetrazole in mice. We also assessed the performance of mice in the rotarod to calculate therapeutic indexes and exploratory activity in the open field. Our results showed that subchronic use of ceftriaxone was neuroprotective in both models, reducing injury in acute ischemia and ischemia/reperfusion in specific layers of retina and leading to a decrease in the seizure severity score. In behavioral experiments, we observed that ceftriaxone increased hyperactivity followed by a decrease in exploratory behavior in the open field, and there was no motor impairment in the rotarod test. We conclude that ceftriaxone may be useful as a tool in the development of new neuroprotective drugs targeting diseases which present a possible dysfunction in the balance of glutamatergic neurotransmission., (© 2020 Wiley Periodicals LLC.)

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA A receptors, binding at a non-benzodiazepine site., Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques., Methods: We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry ( http://www.clinicaltrials.gov ). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome., Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia., Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Introduction: Uncontrolled epilepsy has persisted despite development of numerous antiseizure medications (ASMs) over the past 25 years, and more effective treatments are needed. Cenobamate is a new ASM approved in the US for treatment of adults with focal onset seizures., Areas Covered: This review outlines cenobamate study results from preclinical animal models through phase 2 and 3 clinical studies. Topics include mechanisms of action, pharmacokinetics, efficacy, and safety of cenobamate. Information on dosing, tolerability, and special populations are included to help healthcare providers understand this new ASM., Expert Opinion: Adjunctive cenobamate shows a high level of efficacy in patients with refractory focal epilepsy compared to that reported for other ASMs. Most notable are reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%) with cenobamate in patients with refractory epilepsy despite the concomitant use of 1-3 ASMs. Cenobamate was generally safe and well-tolerated, with a safety profile similar to other ASMs. Due to 3 early cases of DRESS, however, the cenobamate starting dose was lowered and titration rate slowed; no additional cases occurred. If efficacy responses in real-world use reflect what have been observed in clinical studies, cenobamate would be a welcome new treatment option.

Background: Angiotensin receptor blockers (ARBs) reducing inflammation and protecting lung and brain function, could be of therapeutic efficacy in COVID-19 patients., Methods: Using GSEA, we compared our previous transcriptome analysis of neurons injured by glutamate and treated with the ARB Candesartan (GSE67036) with transcriptional signatures from SARS-CoV-2 infected primary human bronchial epithelial cells (NHBE) and lung postmortem (GSE147507), PBMC and BALF samples (CRA002390) from COVID-19 patients., Results: Hundreds of genes upregulated in SARS-CoV-2/COVID-19 transcriptomes were similarly upregulated by glutamate and normalized by Candesartan. Gene Ontology analysis revealed expression profiles with greatest significance and enrichment, including proinflammatory cytokine and chemokine activity, the NF-kappa B complex, alterations in innate and adaptive immunity, with many genes participating in the COVID-19 cytokine storm., Conclusions: There are similar injury mechanisms in SARS-CoV-2 infection and neuronal injury, equally reduced by ARB treatment. This supports the hypothesis of a therapeutic role for ARBs, ameliorating the COVID-19 cytokine storm., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K + levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K + levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

Background: The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [ 99m Tc]Tc-DT1 ([ 99m Tc]Tc-[N 4 -Gly 7 ]NT(7-13)) and [ 99m Tc]Tc-DT5 ([ 99m Tc]Tc-[N 4 - β Ala 7 ,Dab 9 ]NT(7-13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [ 99m Tc]Tc-DT1 and [ 99m Tc]Tc-DT5 in pancreatic cancer models., Methods: The cellular uptake of [ 99m Tc]Tc-DT1 and [ 99m Tc]Tc-DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts., Results: The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [ 99m Tc]Tc-DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; p < 0.0001)., Conclusions: This study has shown the feasibility of optimizing the uptake of [ 99m Tc]Tc-DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.

Purpose: A new series of tetrazole derivatives, which are renowned antimicrobials possessing a five-membered aromatic heterocyclic group, are synthesized herein and subjected to antimicrobial and cytotoxicity screening., Methods: The tetrazole derivatives were synthesized via ultrasonication using Mannich base condensation. Structural verification of the products was performed using IR, 1 H NMR, and 13 C NMR spectroscopy, as well as mass spectroscopic and elemental analyses. The compounds were then screened for antimicrobial and cytotoxic activity against HepG2 (liver), MCF-7 (breast), and HeLa (cervical) cell lines. Inter- and intra-molecular binding interactions were determined using molecular docking studies. The exact binding mode between the most active tetrazole derivatives (ie, 1b, 2a, and 2b) and the proteins (ie, 4OR7, 1AI9, and 4FM9) was established using Autodock Vina 1.1.2 software and compared to the binding mode of the reference compounds (ie, cefazolin, clotrimazole, and fluorouracil)., Results: Compound 1b was extremely active against Enterococcus faecalis relative to the positive control cefazolin. Compounds 1b and 1e were active against Candida albicans and Microsporum audouinii compared to the positive control clotrimazole in antifungal screening. The HepG2 (liver) and MCF-7 (breast) cancer cell lines were particularly susceptible to the synthesized compounds. Compared to the control compound fluorouracil, 2a and 2b were extremely active against all three cancer cell lines. Molecular docking studies showed that 2b exhibited higher binding affinity (-7.8 kcal/mol) to the 4OR7 protein than the control cefazolin (-7.2 kcal/mol)., Conclusion: Generally, 1b, 2a, and 2b exhibited impressive inhibitory capabilities in antibacterial, antifungal, and cytotoxic screenings relative to the reference compounds. The results of the molecular docking studies and both the microbial and anticancer screenings indicate that these novel derivatives could be developed into potential therapeutic agents for medical applications., Competing Interests: The authors have no conflicts of interest to declare., (© 2020 Atef Hatamleh et al.)

HSCs (hepatic stellate cells) contribute to the excessive extracellular matrix (ECM) deposition, inflammatory pathways and crucial cell-cell interactions in hepatic disease leading to fibrosis. P2x7R is considered a potential orchestrater in liver fibrosis. For this reason, this work explored the role of P2x7R in liver fibrosis and the mechanism by which P2x7R in macrophages promotes fibrogenesis. In a model of liver fibrosis induced by administration of thioacetamide (TAA), inhibition of P2x7R with its selective inhibitor A438079 reversed TAA-induced liver damage and fibrosis. The mechanism was linked to inhibition of P2x7R-NLRP3 inflammasome activation and thereby infiltration of macrophages and neutrophils into the liver. This result indicated that the P2x7R-TLR4-NLRP3 axis is involved in the process of TGF-β-mediated ECM deposition in HSCs. Ectopic overexpression of P2x7R lowered the threshold of extracellular matrix (ECM) deposition and maintained HSCs in an activated state. The culture medium of THP-1 macrophages stimulated by LPS/ATP aggravated ECM deposition in HSCs by activating P2x7R. Additionally, IL-1β secreted by LPS / ATP activated macrophages amplified fibrosis. These data indicate that P2x7R plays a key regulative role in the activation and maintenance of HSCs promoted by macrophages. Thus, pharmacological inhibition of P2x7R could be a potential therapeutic mechanism to treat human liver fibrosis., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD)., Methods: After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema)., Results: Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin-eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control., Conclusions: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Background/aims: The persistent existence of pathological cardiac remodeling, resulting from aortic stenosis, is related to poor clinical prognosis after successful transcatheter aortic valve replacement (TAVR). Sacubitril/valsartan (Sac/Val), comprising an angiotensin receptor blocker and a neprilysin inhibitor, has been demonstrated to have a beneficial effect against pathological cardiac remodeling, including cardiac fibrosis and inflammation in heart failure. The aim of this study was to determine whether Sac/Val exerts a cardioprotective effect after pressure unloading in mice., Methods and Results: Male C57BL/6 J mice were subjected to debanding (DB) surgery after 8 weeks (wk) of aortic banding (AB). Cardiac function was assessed by echocardiography, which indicated a protective effect of Sac/Val after DB. After treatment with Sac/Val post DB, decreased heart weight and myocardial cell size were observed in mouse hearts. In addition, histological analysis, immunofluorescence, and western blot results showed that Sac/Val attenuated cardiac fibrosis and inflammation after DB. Finally, our data indicated that Sac/Val treatment could significantly suppress NF-κB signaling and NLRP3 inflammasome activation in mice after relief of pressure overload., Conclusion: Sac/Val exerted its beneficial effects to prevent maladaptive cardiac fibrosis and dysfunction in mice following pressure unloading, which was at least partly due to the inhibition of NLRP3 inflammasome activation.

Large conductance calcium-activated potassium (BK) channels play a crucial role in the repolarization and after-hyperpolarization phases of the cell membrane. The channel openers are also used in treatment of some diseases, including hypo/hyperkalemic periodic paralysis. However, little is known about the effects of BK channels and the channel activators on membrane potentials in skeletal muscle. In addition, the effects of reactive oxygen species (ROS) on BK channels in skeletal muscle are also unknown. Therefore, the aim of this study was to determine the effects of BK channel openers and ROS on membrane potentials in skeletal muscle fibers. For this purpose, resting membrane potentials and action potentials (AP) of frog gastrocnemius muscles were recorded in the presence of commonly used BK channel openers NS1619 and NS11021, H 2 O 2 (a type of ROS), and both using intracellular microelectrode technique. The channel activators significantly and dose-dependently decreased amplitude and increased rise time of AP but did not impact repolarization. The presence of H 2 O 2 plus NS1619 or NS11021 resulted in significant change because the channel openers completely reversed the deleterious effects of hydrogen peroxide on the repolarization phase of AP in skeletal muscle fibers. In the present study, the contributions of BK channel activation and the modulatory role of H 2 O 2 on membrane potentials was demonstrated in skeletal muscle fibers, for the first time. Moreover, it should be noted that BK channel openers should be used in the treatment of reactive oxygen species-induced skeletal muscle diseases.

Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

Aims: We aimed to investigate whether LCZ696 protects against pathological cardiac hypertrophy by regulating the Sirt3/MnSOD pathway., Methods: In vivo , we established a transverse aortic constriction animal model to establish pressure overload-induced heart failure. Subsequently, the mice were given LCZ696 by oral gavage for 4 weeks. After that, the mice underwent transthoracic echocardiography before they were sacrificed. In vitro , we introduced phenylephrine to prime neonatal rat cardiomyocytes and small-interfering RNA to knock down Sirt3 expression., Results: Pathological hypertrophic stimuli caused cardiac hypertrophy and fibrosis and reduced the expression levels of Sirt3 and MnSOD. LCZ696 alleviated the accumulation of oxidative reactive oxygen species (ROS) and cardiomyocyte apoptosis. Furthermore, Sirt3 deficiency abolished the protective effect of LCZ696 on cardiomyocyte hypertrophy, indicating that LCZ696 induced the upregulation of MnSOD and phosphorylation of AMPK through a Sirt3-dependent pathway., Conclusions: LCZ696 may mitigate myocardium oxidative stress and apoptosis in pressure overload-induced heart failure by regulating the Sirt3/MnSOD pathway., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Shi Peng et al.)

Background and Purpose: Angiotensin receptor-NEP inhibitor (ARNi), which includes an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating heart failure with reduced ejection fraction (HF-REF). S086 is a novel single-molecule ARNi that includes the molecular moieties of EXP3174 (the active metabolite of the ARB losartan) and sacubitril (a NEP inhibitor prodrug) in a 1:1 M ratio. We performed preclinical animal model studies to evaluate the efficacy of S086 in treating HF., Experimental Approach: Rat and dog models of myocardial ischemia-induced chronic heart failure were used in this research., Principal Results: The oral administration of S086 dose-dependently lowered the heart weight index, attenuated cardiac fibrosis, and improved left ventricular ejection fraction, shortening fraction, and cardiac output, without effects on hemodynamics in animal models of myocardial ischemia-induced chronic heart failure. A comparable protective effect to LCZ696 was observed for S086 at an equal molar dose in dog models. In addition, S086 was superior to LCZ696 since it significantly reversed the decrease in left ventricular posterior wall end-systolic thickness., Conclusion: This animal study suggests that S086 is effective in treating myocardial ischemia-induced chronic heart failure., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients., (©2020 Wiley Periodicals LLC.)

Uridine 5'-triphosphate (UTP) has an important role as an extracellular signaling molecule that regulates inflammation, angiogenesis, and vascular tone. While chronic hypertension has been shown to promote alterations in arterial vascular tone regulation, carotid artery responses to UTP under hypertensive conditions have remained unclear. The present study investigated carotid artery responses to UTP in spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY). Accordingly, our results found that although UTP promotes concentration-dependent relaxation in isolated carotid artery segments from both SHR and WKY after pretreatment with phenylephrine, SHR exhibited significantly lower arterial relaxation responses compared with WKY. Moreover, UTP-induced relaxation was substantially reduced by endothelial denudation and by the nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine in both SHR and WKY. The difference in UTP-induced relaxation between both groups was abolished by the selective P2Y 2 receptor antagonist AR-C118925XX and the cyclooxygenase (COX) inhibitor indomethacin but not by the thromboxane-prostanoid receptor antagonist SQ29548. Furthermore, we detected the release of PGE 2 , PGF 2α , and PGI 2 in the carotid arteries of SHR and WKY, both at baseline and in response to UTP. UTP administration also increased TXA 2 levels in WKY but not SHR. Overall, our results suggest that UTP-induced relaxation in carotid arteries is impaired in SHR perhaps due to impaired P2Y 2 receptor signaling, reductions in endothelial NO, and increases in the levels of COX-derived vasoconstrictor prostanoids.

Ru (II) compounds have potential application in photodynamic therapy (PDT). In the current study, two Ru (II) compounds based on the auxiliary ligand 2,2'-bipyridine (bipy) by changing main ligands 5-(2-pyridyl) tetrazole (Hpytz) and di(2H-tetrazol-5-yl) amine (H 2 datz) have been successfully synthesized and characterized, [Ru (pytz)(bipy) 2 ][PF 6 ] (1) and [Ru(Hdatz)(bipy) 2 ][PF 6 ] (2). These compounds can form nanoparticles (NPs) by nano-precipitation. And [Ru(pytz)(bipy) 2 ][PF 6 ] NPs with a lower half maximal inhibitory concentration (IC 50 ) of 37 μg/mL on HeLa cells than that of [Ru(Hdatz)(bipy) 2 ][PF 6 ] NPs (65 μg/mL). Meanwhile, negligible dark toxicity has been also observed for these NPs even under high concentrations. The results show that [Ru(pytz)(bipy) 2 ][PF 6 ] (1) and [Ru(Hdatz)(bipy) 2 ][PF 6 ] (2) NPs can inhibit cell proliferation in vitro, and may be potential candidates for photodynamic therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Obesity is a significant breast cancer (BC) risk factor and is associated with 20-40% increased risk in obese post-menopausal women compared to their lean counterparts. Several obesity-related metabolic dysregulations have been linked to BC risk, including overactivation of the renin-angiotensin system (RAS). Currently, RAS inhibitors including angiotensin converting enzyme inhibitor (ACEi) and AT1 receptor blockers (ARBs), are used as safe and effective anti-hypertensive therapies in BC patients. However, it is uncertain how inhibition of RAS in adipose tissue impacts obesity-BC crosstalk. We hypothesized that adipose RAS inhibition will reduce BC cell motility and inflammation. We determined (1) the direct effects of Ang II, ACEi (captopril; Cap) or ARB (telmisartan; Tel) on receptor positive MCF-7 and receptor triple negative MDA-MB-231 cells; and (2) the effects of conditioned media (CM) from human mesenchymal stem cells differentiated into adipocytes, which were pretreated with RAS inhibitors, on BC cells. We demonstrated that direct treatments of BC cells with Ang II, Cap or Tel did not alter inflammatory cytokines in either BC cell line. However, CM from Ang II-pretreated adipocytes significantly increased secretion of pro-inflammatory markers at protein level. RAS inhibitors reduced their secretion in MDA-MB-231, but not in MCF-7 cells. Additionally, CM from adipocytes treated with RAS inhibitors significantly reduced markers of inflammation, fat synthesis, and angiogenesis in both BC cell lines. Furthermore, CM from ACEi pretreated adipocytes reduced cell motility in both BC cell lines. Findings from our study indicate an important role of adipose RAS inhibition in adipocyte and BC cell crosstalk., (Copyright © 2020. Published by Elsevier Inc.)

Background: Hypertension is a disease with significant clinical and socio-economic consequences. The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. Diuretics have proven useful for the prevention of cardiovascular complications in addition to a long history of safety and efficacy. The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension., Methods: A comprehensive literature search was conducted through electronic databases PubMed, MEDLINE, Scopus, PsyInfo, Cochrane, eLIBRARY.ru, http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu in July 2020 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. Changes in systolic and diastolic blood pressure (BP) expressed as a weighted mean difference (WMD) were our primary outcomes. The random-effects method was chosen as the primary analysis and results were presented with a 95% confidence interval (CI). Sensitivity analysis was performed and bias was assessed., Results: Our search returned 2745 titles. Of them, 51 full-text articles remained to be subjected to assessment. Comparisons of ARB/HCTZ versus ARB showed changes in BP of -6.89 (-8.09, -5.69) mmHg for systolic BP and - 3.67 (-4.15, -3.19) mmHg for diastolic BP. For the ARB/CTLD versus ARB/HCTZ comparison changes were - 6.30 (-7.30, -5.29) mmHg for systolic BP and - 3.57 (-4.17, 2.98) mmHg for diastolic BP., Conclusion: Our analysis suggests a small but significant favor for CTLD in blood pressure control when compared to HCTZ. We believe it should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB although further research is required.

Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca 2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen Ⅰ and Ⅲ, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and I caL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen Ⅰ and Ⅲ, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Ca v 1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca 2+ concentration increased and I CaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The ionic mechanisms controlling the resting membrane potential (RMP) in superior cervical ganglion (SCG) neurons have been widely studied and the M-current (I M , KCNQ) is one of the key players. Recently, with the discovery of the presence of functional TREK-2 (TWIK-related K + channel 2) channels in SCG neurons, another potential main contributor for setting the value of the resting membrane potential has appeared. In the present work, we quantified the contribution of TREK-2 channels to the resting membrane potential at physiological temperature and studied its role in excitability using patch-clamp techniques. In the process we have discovered that TREK-2 channels are sensitive to the classic M-current blockers linopirdine and XE991 (IC 50 = 0.310 ± 0.06 µM and 0.044 ± 0.013 µM, respectively). An increase from room temperature (23 °C) to physiological temperature (37 °C) enhanced both I M and TREK-2 currents. Likewise, inhibition of I M by tetraethylammonium (TEA) and TREK-2 current by XE991 depolarized the RMP at room and physiological temperatures. Temperature rise also enhanced adaptation in SCG neurons which was reduced due to TREK-2 and I M inhibition by XE991 application. In summary, TREK-2 and M currents contribute to the resting membrane potential and excitability at room and physiological temperature in the primary culture of mouse SCG neurons.

Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone., Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death)., Methods: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint., Results: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates., Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.