Blocker Treatment Research Articles

In vivo and in vitro impact of atorvastatin against myocardial ischaemia-reperfusion injury by upregulation of silent information regulator l and attenuation of endoplasmic reticulum stress-induced apoptosis

We aimed to investigate the effects and mechanism of Atorvastatin on Myocardial Ischaemia-Reperfusion Injury in vitro and in vivo. The effects of Atorvastatin on Silent information regulator l (SIRT1) and endoplasmic reticulum (ER) stress were investigated in Myocardial ischaemia-reperfusion (MI/R) injury rat model and hypoxia/reoxygenation (H/R)-treated H9c2 cells. Pathological changes, inflammatory and heart injury markers, cell apoptosis and cell death, SIRT1 and cleaved Caspase-12 expressions, and ER stress relative proteins were measured through HE, enzyme-linked immunosorbent assay, quantitative TUNEL and flow cytometry, immunofluorescence and Western blotting with the assistance of the SIRT1 specific inhibitor EX527 and ER stress pathway blocker treatment. The results of our study demonstrated that atorvastatin treatment attenuated MI/R and H/R mediated inflammatory and heart injury markers, cell apoptosis and cell death, SIRT1 and cleaved Caspase-12 expressions, and ER stress relative protein levels. Finally, we found that atorvastatin reversed SIRT1 expression and blockade the ER stress pathway and increase the cardiomyocytes survival rate in the presence of MI/R and H/R. Our findings provided a new rationale for subsequent academic and clinical research on MI/R injury.

Abstract 5010: Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment

Abstract Alternative splicing (AS) events play a crucial role in the tumorigenesis and progression of cancer. Transcriptome data and Percent Spliced In (PSI) values of ovarian cancer patients were downloaded from TCGA database and TCGA SpliceSeq. Totally we identified 1,472 AS events that were associated with survival of ovarian serous cystadenocarcinoma (OV) and exon skipping (ES) was the most important type. Univariate and multivariate Cox regression analysis were performed to identify survival-associated AS events and developed the prognostic model based on 11-AS events. The immune cells and different response to cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers in low-risk and high-risk group of OV patients were analyzed. Ten kinds of immune cells were found up-regulated in low-risk group. Activated B cell, natural killer T cell, natural killer cell and regulatory T cell were associated with survival of OV. The patients in low-risk group had good response to CTLA-4 and PD-1 blockers treatment. Moreover, a regulatory network was established according to the correlation between AS events and splicing factors (SFs). The present study provided valuable insights into the underlying mechanisms of OV. AS events that were correlated with the immune system might be potential therapeutic targets. Citation Format: Guixi Zheng. Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5010.

The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

P208 THE TREATMENT WITH BETA–BLOCKERS AFTER MYOCARDIAL INFARCTION WITHOUT REDUCED EJECTION FRACTION (REBOOT) TRIAL. CURRENT STATUS

Abstract Background There is a lack of evidence regarding the benefits of maintenance β–blocker (BB) treatment in post–acute AMI patients (pts) without reduced LVEF in the era of invasive management. Design and Trial Status REBOOT is an independent multinational pragmatic, controlled, randomized, open–label, with blinded endpoint adjudication clinical trial testing the benefits of BB maintenance therapy in post–AMI pts (either with or without ST segment elevation) discharged with LVEF >40%. Patients ≥18 years (yr) old undergoing invasive management during admission and without history of heart failure (HF) are eligible to participate. At discharge, pts are 1:1 randomized to either receive BB (agent and dose chosen by the treating physician) or no BB therapy. The primary endpoint is a composite of “all–cause death, nonfatal reAMI, or HF hospitalization” over a minimum follow–up period of 2 yr. Key secondary endpoints are: a) the incidence rate of each individual component of the composite endpoint; b) cardiovascular death; c) admission for sustained ventricular tachycardia/ventricular fibrillation; and d) admission for atrial fibrillation. Events will be adjudicated by a blinded committee. A sample size of 8468 pts (728 events) was estimated to provide a power of 85% to detect a relative risk reduction of 20% (incidence of primary endpoint in control 10%) and assuming 5% withdrawals. Statistical analyses will be conducted according to the intention–to–treat principle, although a pre–specified per–protocol analysis will also be performed. The Spanish National Center for Cardiovascular Research (CNIC) is the sponsor of the trial, which has no external funding. CNIC coordinates ≥75 Spanish centers, while Istituto di Ricerche Farmacologiche Mario Negri IRCCS coordinate 33 Cardiology Centers distributed in 10 Italian regions. The first pt was included in Spain in October 2018, in Italy in January 2019. The end of enrollment is anticipated in December 2022. At 09 December 2021, 5669 pts had been enrolled from which 1263 in Italy (Figure). Pts baseline characteristics are described in the Table. Hospital admission data for COVID–19 pre and post randomization were also recorded since June 2020. Conclusions The REBOOT trial (NCT03596385) will fill the existing scientific gap on the efficacy of β–BB after AMI in pts with LVEF > 40% and no HF who are treated according to current standard–of–care. REBOOT trial results might have an impact on clinical practice guidelines.

Are beta blockers effective in preventing stroke-associated infections? - a systematic review and meta-analysis.

Background: Excessive sympathoexcitation could lead to stroke associated infection. Inhibiting sympathetic excitation may reduce the infection risk after stroke. Thus, the present study aimed to determine the protective effect of beta blockers on stroke associated infection through systematic review and meta-analysis.Methods: A systematic search of multiple databases were performed up to February 2022. The included studies required beta blockers therapy in stroke patients and assessed the incidence of stroke-associated infections. Outcomes of interest included infections, pneumonia, urinary tract infection and sepsis. Random-effects model was used for analysis. Heterogeneity was evaluated using I2 statistics and publication bias was evaluated by the funnel plot.Result: A total of 83 potentially relevant publications was identified in the initial search. Six studies met the inclusion criteria for meta-analysis. The risk of bias in the included articles satisfies the quality requirement of meta-analysis. No significant associations between beta blockers therapy and the prevention of stroke associated infection, stroke associated pneumonia and septicemia were found, However, subgroup analyses revealed an association between beta blockers treatment and the increased risk of post-stroke urinary tract infection or stroke associated pneumonia in some stroke patients (OR = 1.69 [1.33, 2.14], P < 0.0001; OR = 1.85 [1.51, 2.26], P < 0.0001).Conclusion: Due to the lack of robust evidence, this meta-analysis may not support the preventive effect of beta blockers on stroke associated infection. But beta blockers treatment may be associated with development of post-stroke urinary tract infection and stroke associated pneumonia in some stroke patients.

In silico comparison between the mutated and wild type androgen receptors and their influence on the selection of optimum androgenic receptor blocker for treatment of prostate cancer

Background: Prostate cancer is a disease that occurs in men aged more than 50 years. In Iraq, 8.89 men per 100,000 population suffer from prostate cancer, with the incidence being 14,016 cases and mortality being 6,367 cases. Despite advances in treatment against prostate cancer, it can become resistant to drugs. Therefore, the aim of current study was to search and identify binding sites for the repositioning of drugs by computational methods (docking). Methods: Based on the protein structure of the wild androgen receptor, the analysis parameters (22x22x22 on the X, Y, and Z axes) were established. Results: The interactions of the natural ligands with androgen receptor were 10.0 (testosterone) and 10.8 (dihydrotestosterone) while mutated androgen receptor (T877A) had a low affinity with testosterone and dihydrotestosterone (-5.3 and -6.7, respectively). In the interactions of both receptors with the reported inhibitors (antagonists), a decrease with Bicalutamide (-8.3 and -4.3, respectively) and an increase in affinity with Flutamide and Nilutamide (-7.7 and 8.6, wild AR; -8.7 and -9.3 AR T877A) were observed. As for Enzalutamide and Apalutamide (second-generation antagonists), the change was minimal between wild androgen receptor and T877A (-7.6 and -7.7; -7.3 and -7.3, respectively). The change in the affinity of the ligands with androgen receptor and androgen receptor T877A shows how a mutation alters the bonds between these molecules. Conclusion: The identification of key sites and potent inhibitors against abnormal androgen receptor functions will enrich prostate cancer treatments.

Lack of renoprotective effects of targeting the endothelin A receptor and (or) sodium glucose transporter 2 in a mouse model of Type 2 diabetic kidney disease.

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1mg/kg/day), ET-A blocker (atrasentan (atra), 5mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age. At 10 weeks of age, no differences were observed in body weight, blood glucose or urinary albumin excretion among the four groups. At 16 and 22 weeks of age, body weight was lower and blood glucose levels higher in the vehicle and atra groups compared with dapa- and dual-treated groups. No notable differences were observed among the four groups in urinary albumin excretion at weeks 16 and 22. Histological analysis showed mild glomerulosclerosis and tubular injury (<5%) in all four groups with reduced glomerulosclerosis in the dual treatment group compared with vehicle. Individual or combined treatment with an SGLT2 inhibitor and (or) an ET-A antagonist did not confer renoprotective effects in this model.

Effects of losartan on glandular epithelial prostatic hyperplasia in spontaneously hypertensive rats

ABSTRACT Introduction Benign prostatic hyperplasia (BPH) and benign prostatic enlargement (BPE) are common disorders in aging men and cause lower urinary tract symptoms. Hypertension induces atherosclerosis in the blood vessels of the lower urinary tract, subsequently following by the development of BPH and BPE. Clinical study demonstrated that anti-hypertensive drug angiotensin II type 1 receptor blocker (ARB) treatment improved storage and voiding scores in male patients with hypertension, whereas other antihypertensive drugs were not effective. ARB could improve prostatic hyperplasia independent of reducing blood pressure. Spontaneously hypertensive rats (SHRs) are widely used as genetically hypertensive model. SHRs also demonstrate decreased prostatic blood flow and develop glandular epithelial hyperplasia and morphological abnormalities in the ventral prostate. Objective We examined the effects of an ARB, losartan on glandular epithelial prostatic hyperplasia in SHRs. Methods Thirty-six-weeks old male SHRs were orally treated with losartan (3 or 10 mg/kg/day) or vehicle once daily for 18 weeks. Wistar Kyoto rats (WKYs) were treated with vehicle were used as controls (n = 8). After the oral treatment, effects of losartan were evaluated by measuring prostate weight, blood pressure, and prostatic blood flow. The tissue levels of malondialdehyde (oxidative stress marker; MDA), interleukin-6 (inflammatory cytokine; IL-6), and basic fibroblast growth factor (bFGF) levels in ventral prostate were measured by colorimetric assay and ELISA assay. Histological analysis for the ventral prostate was performed by hematoxylin and eosin (HE) staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. The glandular epithelial area was determined by HE staining. TUNEL assay was performed to quantify the degree of apoptosis. The statistical differences were determined using one-way analysis of variance followed by the Tukey-Kramer test. Histological data were analyzed using the nonparametric Kruskal-Wallis test followed by the Mann-Whitney U test with Bonferroni's correction for multiple comparison. Results Body weight did not significantly differ among the groups. The vehicle treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow compared to the vehicle treated WKYs. Treatment with losartan significantly decreased PBR and improved prostatic blood flow and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. Conclusion Chronic losartan treatment could improve glandular epithelial prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might improve not only hypertension but also prostatic hyperplasia in humans. Disclosure Work supported by industry: no.

Enalapril associated with combined training is more effective in reducing SBP and improve baroreflex sensitivity than drug therapies alone in hypertensive rats

High blood pressure is the leading risk factor to development of cardiovascular disease worldwide. Diuretic and angiotensin‐converting enzyme blockers treatment is widely used for its efficiency in reducing blood pressure (BP). Combined physical training (aerobic + resistance) is recommended for hypertensive patients; however, it is not yet clear whether the combination of antihypertensive treatment with this training modality results in additional benefits. Therefore, the aim of this study was to compare the effects of combined training with different drug treatments on systolic BP (SBP) and baroreflex sensitivity (BRS) of spontaneously hypertensive rats (SHR). Twenty‐eight males SHR rats were divided into four groups (n=7/group): HS (sedentary hydrochlorothiazide), HT (trained hydrochlorothiazide), ES (sedentary enalapril) and ET (trained enalapril). Drugs were administered in drinking water (enalapril 3 mg/kg/day and hydrochlorothiazide 30 mg/kg/day). All groups underwent exercise testing before and after 2 months. The trained groups performed combined training 3 times a week, being aerobic and resistance at same session, moderate intensity. The SBP was analyzed by caudal plethysmography before starting the drugs and 24h after the last training session. BRS was analyzed by response to phenylephrine and sodium nitroprusside. Both trained groups increased maximal aerobic exercise test (p&lt;0.0001) and resistance exercise test (HT vs. HS, p=0.02; ET vs. ES, p&lt;0.0001) versus the sedentary groups at the end of the protocol. There was no difference in the initial SBP between the groups (HS 176 ± 4.3, HT 175 ± 3, ES 173 ± 1.4 and ET 183 ± 3 mmHg). There were reductions in SBP in the HT (161 ± 1.3 mmHg), ES (159 ± 4.4 mmHg) and ET groups (147 ± 3.3 mmHg) at the end of the protocol. In addition, the trained group associated with enalapril treatment further reduced SBP when compared to the trained hydrochlorothiazide group (ET vs. HT, p = 0.02). Regarding BRS, there was no difference in tachycardic response between groups; however, ET group (‐2.8 ± 0.5 bpm/mmHg) showed increased bradycardic responses comparing with ES group (‐1.8 ± 0.1 bpm/mmHg). Therefore, the data support that the association of combined exercise training with enalapril treatment and is more effective in reducing SBP and improving BRS than the combination with hydrochlorothiazide treatment. It is noteworthy that the training proposed in this study was performed only three times a week, getting closer to clinical recommendations, and being enough for induce additional benefits to classical drug therapies in functional capacity and blood pressure control in an experimental model of hypertension.

Angiotensin-converting enzyme 2 and transmembrane protease serine 2 in female and male patients with end-stage kidney disease.

BackgroundIndividuals with chronic kidney disease are affected by acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) due to multiple comorbidities and altered immune system. The first step of the infection process is the binding of SARS‐CoV‐2 with angiotensin‐converting enzyme 2 (ACE2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that circulating soluble ACE2 levels, as well as the expressions of ACE2 and TMPRSS2 in the microvasculature, are increased in patients with end‐stage kidney disease (ESKD).MethodsA total of 210 participants were enrolled, representing 80 ESKD patients and 73 non‐CKD controls for soluble ACE2, and 31 ESKD and 26 non‐CKD controls for vasculature and fat tissue bioassays. We have assessed ACE2 expression in blood using ELISA and in tissue using immunofluorescence.ResultsSoluble ACE2 levels were higher in ESKD patients compared to controls; however, there is no sex difference observed. In ESKD and controls, soluble ACE2 positively correlated with Interleukin 6 (IL‐6) and C‐reactive protein (CRP), respectively. Similarly, ACE2 tissue expression in the vasculature was higher in ESKD patients; moreover, this higher ACE2 expression was observed only in male ESKD patients. In addition, TMPRSS2 expression was observed in vessels from males and females but showed no sex difference. The expression of ACE2 receptor was higher in ESKD patients on ACE‐inhibitor/angiotensin blocker treatment.ConclusionESKD is associated with increased ACE2 levels in the circulation and pronounced in male vasculature; however, further studies are warranted to assess possible sex differences on specific treatment regime(s) for different comorbidities present in ESKD.

Positive association between calcium channel blocker treatment and persistent type II endoleak.

Type II endoleaks are the most common complication occurring after endovascular abdominal aortic aneurysm repair (EVAR). The aims of our study were to evaluate the impact of persistent type II endoleak on sac dynamics post-EVAR, and to study the association between non-anatomical factors including polymorphisms associated with abdominal aortic aneurysm (AAA) and persistent type II endoleak. The cohort comprises 210 patients undergoing EVAR between January 2010 and December 2018. A persistent type II endoleak was defined as any type II endoleak lasting longer than six months and included also a type II endoleak diagnosed after six months or more post-EVAR during the 36-month follow-up period confirmed with CT-angiography. Anteroposterior AAA maximum diameter and AAA volume were measured pre-EVAR and 36 months post-EVAR using CT-angiographic pictures. Sac progression was defined as at least 5 mm increase, sac regression as at least 5 mm decrease in the sac diameter in relation to the preprocedural diameter. Sociodemographic information, comorbidities, treatment, laboratory parameters, selected anatomical and genetic factors were all analyzed to determine their impact on persistent type II endoleak. The adjustments included age, hypertension, diabetes mellitus, dyslipidemia, sex, smoking in multivariate analyses. When postprocedural diameter and volume were evaluated, adjustments included also preprocedural diameter/volume. After exclusion, 178 patients with mean age 72.4±7.60 years remained for analysis. Persistent type II endoleak was found in 27.5% of patients (N.=49) and 2.94-times increased risk of sac progression in multivariate analysis (P=0.033). In multivariate analysis, AAA diameter in patients with persistent type II endoleak was 4.31 mm greater than in patients without (B=4.31; P=0.014); and its presence was also associated with 22.0 cm3 greater sac volume (B=22.0; P=0.034) compared to patients without persistent type II endoleak. Treatment with calcium channel blockers increased risk of persistent type II endoleak 2.11-times in multivariate analysis (OR=2.11; 95% CI: 1.05-4.25; P=0.037). No association between persistent type II endoleak and selected polymorphisms associated with AAA and other observed factors were found. Risk of persistent type II endoleak was more than doubled in patients taking calcium channel blockers. Patients with persistent type II endoleak had greater anteroposterior sac diameter and sac volume compared to patients without persistent type II endoleak.

Effects of Antihypertensive Drugs on Thyroid Function in Type 2 Diabetes Patients With Euthyroidism.

Objective: There is little literature about whether antihypertensive drugs would affect thyroid function in patients with euthyroid type 2 diabetes, which was significant in maintaining a proper balance of thyroid function. A retrospective cohort study was conducted to evaluate the influence of antihypertensive drugs on thyroid function in patients with type 2 diabetes with euthyroidism. Design and Methods: The study involved dividing 698 patients with antihypertensive monotherapy into five groups according to the antihypertensive drugs they were treated with. Antihypertensive drugs included in this study were β-blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB). The clinical data and thyroid function level between or within groups were compared. Multiple logistic regression analysis was conducted to evaluate the association of antihypertensive drugs with thyroid function level. Results: Selective β1- adrenergic receptor blockers treatment was related to thyroid-stimulating hormone (TSH), increasing in patients with diabetes and euthyroidism as shown by multiple logistic regression analysis. The association existed after adjustment for confounding factors. No significant influence on thyroid function was found among other antihypertensive drugs. Conclusion: These data show the TSH-lifting effect of selective β1-adrenergic receptor blockers in patients with type 2 diabetes with euthyroidism.

Comparative peripheral edema for dihydropyridines calcium channel blockers treatment: A systematic review and network meta-analysis.

Dihydropyridine calcium channel blockers (DHPCCBs) are widely used to treat hypertension and chronic coronary artery disease. One common adverse effect of DHPCCBs is peripheral edema, particularly of the lower limbs. The side effect could lead to dose reduction or discontinuation of the medication. The combination of DHPCCBs and renin‐angiotensin system blockers has shown to reduce the risk of DHPCCBs‐associated peripheral edema compared with DHPCCBs monotherapy. We performed the current systematic review and network meta‐analysis of randomized controlled trials (RCTs) to estimate the rate of peripheral edema with DHPCCBs as a class and with individual DHPCCBs and the ranking of the reduction of peripheral edema. The effects of renin‐angiotensin system blockers on DHPCCBs network meta‐analysis were created to analyze the ranking of the reduction of peripheral edema. A total of 3312 publications were identified and 71 studies with 56,283 patients were included. Nifedipine ranked highest in inducing peripheral edema (SUCRA 81.8%) and lacidipine (SUCRA 12.8%) ranked the least. All DHPCCBs except lacidipine resulted in higher relative risk (RR) of peripheral edema compared with placebo. Nifedipine plus angiotensin receptor blocker (SUCRA: 92.3%) did not mitigate peripheral edema and amlodipine plus angiotensin‐converting enzyme inhibitors (SUCRA: 16%) reduced peripheral edema the most. Nifedipine ranked the highest and lacidipine ranked the lowest amongst DHPCCBs for developing peripheral edema when used for cardiovascular indications. The second or higher generation of DHPCCBs combination with ACEIs or ARBs or diuretics lowered the chance of peripheral edema development compared to single DHPCCB treatment.

Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment

Alternative splicing (AS) events play a crucial role in the tumorigenesis and progression of cancer. Transcriptome data and Percent Spliced In (PSI) values of ovarian cancer patients were downloaded from TCGA database and TCGA SpliceSeq. Totally we identified 1472 AS events that were associated with survival of ovarian serous cystadenocarcinoma (OC) and exon skipping (ES) was the most important type. Univariate and multivariate Cox regression analysis were performed to identify survival-associated AS events and developed the prognostic model based on 11-AS events. The immune cells and different response to cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers in low-risk and high-risk group of OC patients were analyzed. Ten kinds of immune cells were found up-regulated in low-risk group. Activated B cell, natural killer T cell, natural killer cell and regulatory T cell were associated with survival of OC. The patients in low-risk group had good response to CTLA-4 and PD-1 blockers treatment. Moreover, a regulatory network was established according to the correlation between AS events and splicing factors (SFs). The present study provided valuable insights into the underlying mechanisms of OC. AS events that were correlated with the immune system might be potential therapeutic targets.

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.

Effects of dibenzylbutyrolactone lignans arctigenin and trachelogenin on the motility of isolated rat ileum

Dibenzylbutyrolactone-type lignans are phenolic compounds of medical importance. The purpose of the study was to determine the effects of two such lignans, arctigenin and trachelogenin on the motility of isolated rat ileum and obtain indications on their mechanism of action. They were isolated from Arctium lappa and Cirsium arvense, respectively, which have been used traditionally to treat gastrointestinal disorders. 1–1.5 cm long segments of distal ileum were obtained from adult male Wistar rats. The intestinal segments were suspended vertically in a well-aerated organ-bath according to Magnus mounting method. The intestinal motility was monitored for 30 min before treatment to obtain the baseline, followed by treatment with 1 µM, 10 µM, 20 µM and 40 µM concentrations of arctigenin and 0.5 µM, 1 µM, 10 µM and 20 µM of trachelogenin concentrations. The amplitude, tone, and period of spontaneous contractions were measured after 15 and 30 min of treatment. To investigate their mechanism of action, cholinergic, glutamatergic, adrenergic antagonists and compounds inhibiting nitric oxide synthase and L-type calcium channels were also tested. Arctigenin and trachelogenin decreased the frequency of contractions in a dose-dependent manner. At the concentration of 20 µM and 40 µM of trachelogenin and arctigenin, respectively, there was a marked alteration in spontaneous contraction pattern with an observable increase in the period time. This activity was comparable to 0.5 µM nifedipine (L-type calcium channel blocker) treatment. Our results demonstrate relaxant effect of arctigenin and trachelogenin on the ileum motility that may be mediated by L-type calcium ion channel blockade.

Neutrophil percentage‐to‐albumin ratio and monocyte‐to‐lymphocyte ratio as predictors of free‐wall rupture in patients with acute myocardial infarction

BackgroundsFree‐wall rupture (FWR) has a high mortality rate. We aimed to find sensitive predictive indicators to identify high‐risk FWR patients by exploring the predictive values of neutrophil percentage‐to‐albumin ratio (NPAR) and monocyte‐to‐lymphocyte ratio (MLR) on patients with acute myocardial infarction (AMI).Methods76 FWR patients with AMI were collected, and then 228 non‐CR patients with AMI were randomly selected (1:3 ratio) in this retrospective study. The independent influencing factors of FWR were evaluated by univariate and multivariate logistic regression analysis. The receiver‐operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of NPAR and MLR for FWR.ResultsAccording to the results of multivariate logistic regression analysis, emergency percutaneous coronary intervention (PCI) (OR = 0.27, 95% CI: 0.094–0.751, p = 0.012), angiotensin‐converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) treatment (OR = 0.17, 95% CI: 0.044–0.659, p = 0.010), NPAR (OR = 2.69, 95% CI: 1.031–7.044, p = 0.043), and MLR (OR = 5.99, 95% CI: 2.09–17.168, p = 0.001) were the influencing factors of the FWR patients with AMI, independently. Additionally, the NPAR and MLR were the predictors of FWR patients, with AUC of 0.811 and 0.778, respectively (both p < 0.001).ConclusionsIn summary, the emergency PCI and ACEI/ARB treatment were independent protective factors for FWR patients with AMI, while the increase of MLR and NPAR were independent risk factors. What's more, NPAR and MLR are good indicators for predicting FWR.

Risk and protective factors of acute kidney injury in decompensated cirrhotic patients with ascites on tolvaptan.

Background and AimAcute kidney injury (AKI) is a life‐threatening complication of liver cirrhosis. Here, we evaluated the risk factors and characteristics of AKI in cirrhosis.Patients/MethodsThis was a single‐center retrospective study. A total of 199 Japanese patients with decompensated liver cirrhosis (104 men, median age 61 years) were enrolled and received tolvaptan orally. Survival rates and new onset of AKI were monitored, and risk factors were evaluated.ResultsForty‐six patients (23.1%) suffered an AKI complication and exhibited significantly poorer survival (P < 0.01). The rates of hepatic encephalopathy (P < 0.01) and chronic kidney disease (CKD; P = 0.02) were significantly increased in patients with AKI. The rate of proton pump inhibitor (PPI)/H2 blocker treatment (P = 0.04) was significantly lower, whereas that of ascites drainage was significantly higher in the AKI cases (P < 0.01). The AKI risk was significantly increased in patients with hepatic encephalopathy (HR 4.18, 95% CI 1.618–10.771). In contrast, the incidence of AKI was significantly lower in patients with a higher serum albumin level (HR 0.36, 95% CI 0.142–0.914, P = 0.03). Treatment with PPI/H2 blockers (HR 0.30, 95% CI 0.126–0.711, P < 0.01) or kanamycin/rifaximin (HR 0.26, 95% CI 0.075–0.929, P = 0.04) was significantly associated with a reduced risk of AKI development.ConclusionsAKI incidence was increased in patients with decreased liver function and was associated with poor survival. PPI/H2 blocker or kanamycin/rifaximin treatment may reduce the risk of AKI.

Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment for Post Infarct Angina in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries: A MINOCA-BAT Sub Study Rationale and Design.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients—The MINOCA BAT post infarct angina sub study.Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months.Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years.Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

Cellular and metabolic effects of renin-angiotensin system blockade on glycogen storage disease type I nephropathy

Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc−/− mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc−/− mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.