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International Journal of Molecular... Aug 2020Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and... (Review)
Review
Basal cell carcinoma (BCC) is the most common type of carcinoma worldwide. BCC development is the result of a complex interaction between environmental, phenotypic and genetic factors. However, despite the progress in the field, BCC biology and mechanisms of resistance against systemic treatments have been poorly investigated. The aim of the present review is to provide a revision of BCC histological and molecular features, including microRNA (miRNA) dysregulation, with a specific focus on the molecular basis of BCC systemic therapies. Papers from the last ten years regarding BCC genetic and phenotypic alterations, as well as the mechanism of resistance against hedgehog pathway inhibitors vismodegib and sonidegib were included. The involvement of miRNAs in BCC resistance to systemic therapies is emerging as a new field of knowledge.
Topics: Anilides; Biphenyl Compounds; Carcinoma, Basal Cell; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; MicroRNAs; Pyridines
PubMed: 32759706
DOI: 10.3390/ijms21155572 -
Journal of Clinical Hypertension... Mar 2022Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no...
Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no prospective study about the effect and safety of SV on resistant hypertension and myocardial work in hemodialysis patients. In this single-center, prospective, before-after study, enrolled patients were endured with resistant hypertension for more than 6 months. Participants were initially instructed to take SV 50 mg twice daily, and the dosage was gradually increased up to 100 mg twice daily. The primary outcomes were blood pressure (BP) control, N-terminal pro-B-type natriuretic peptide (NT-proBNP), myocardial work (MW), fatigue and life quality. In addition, the adverse events were also recorded in this cohort. A total of 18 patients (34-64 years old) was finally enrolled and completed in this study. The SV-based regimen provided significantly mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-20.7/-8.3 mm Hg), respectively. The cardiac remodeling parameters were partially improved. Compared to the baseline, NT-proBNP was significantly reduced at week 4 (8119.50 [3710.75, 29300] pg/ml to 7216.50 [4124.75, 17455.00] pg/ml, p = .046), which was much lower at week 12 (3130.50 [2244.50, 9565.70] pg/ml, p = .037). Global MW index was higher at week 12 compared to the baseline (p = .026). MW efficiency was also improved accordingly compared to the baseline, even though the statistical difference was not significant (p = .226). Life quality and fatigue were improved at week 12 compared to the baseline (all p = .000). There was no serious adverse events were observed. SV safely and effectively controlled resistant hypertension and improved MW as well as life quality in hemodialysis patients.
Topics: Adult; Aminobutyrates; Biphenyl Compounds; Double-Blind Method; Drug Combinations; Fatigue; Heart; Humans; Hypertension; Middle Aged; Prospective Studies; Renal Dialysis; Valsartan
PubMed: 35099841
DOI: 10.1111/jch.14422 -
Journal of the American Heart... May 2022Background Sacubitril/valsartan (S/V) demonstrated significant effects in improving left ventricular performance and remodeling in patients with heart failure with... (Meta-Analysis)
Meta-Analysis Review
Effect of Sacubitril/Valsartan on the Right Ventricular Function and Pulmonary Hypertension in Patients With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis of Observational Studies.
Background Sacubitril/valsartan (S/V) demonstrated significant effects in improving left ventricular performance and remodeling in patients with heart failure with reduced ejection fraction. However, its effects on the right ventricle remain unclear. This systematic review and meta-analysis aimed to assess the impact of S/V on right ventricular function and pulmonary hypertension. Methods and Results We searched PubMed, Embase, Cochrane Library, and Web of Science from January 2010 to April 2021 for studies reporting right ventricular and pulmonary pressure indexes following S/V treatment. The quality of included studies was assessed using the Newcastle-Ottawa scale. Variables were pooled using a random-effects model to estimate weighted mean differences with 95% CIs. We identified 10 eligible studies comprising 875 patients with heart failure with reduced ejection fraction (mean age, 62.2 years; 74.0% men), all of which were observational. Significant improvements on right ventricular function and pulmonary hypertension after S/V initiation were observed, including tricuspid annular plane systolic excursion (weighted mean difference, 1.26 mm; 95% CI, 0.33-2.18 mm; =0.008), tricuspid annular peak systolic velocity (weighted mean difference, 0.85 cm/s; 95% CI, 0.25-1.45 cm/s; =0.005), and systolic pulmonary arterial pressure (weighted mean difference, 7.21 mm Hg; 95% CI, 5.38-9.03 mm Hg; <0.001). Besides, S/V had a significant beneficial impact on left heart function, which was consistent with previous studies. The quadratic regression model revealed a certain correlation between tricuspid annular plane systolic excursion and left ventricular ejection fraction after excluding the inappropriate data (=0.026). Conclusions This meta-analysis verified that S/V could improve right ventricular performance and pulmonary hypertension in heart failure with reduced ejection fraction, which did not seem to be fully dependent on the reverse remodeling of left ventricle. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021247970.
Topics: Aminobutyrates; Biphenyl Compounds; Drug Combinations; Female; Heart Failure; Humans; Hypertension, Pulmonary; Male; Middle Aged; Stroke Volume; Valsartan; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Function, Right
PubMed: 35470677
DOI: 10.1161/JAHA.121.024449 -
Journal of Clinical Hypertension... Mar 2023This study assessed the efficacy and safety of sacubitril/valsartan in 23 hemodialysis patients with hypertension (mean age 70 years; male 69.6%) after switching from...
This study assessed the efficacy and safety of sacubitril/valsartan in 23 hemodialysis patients with hypertension (mean age 70 years; male 69.6%) after switching from azilsartan, an angiotensin receptor blocker. Both at baseline and 3 months after the start of sacubitril/valsartan treatment, home blood pressure (BP), BP values during hemodialysis, and N-terminal pro-brain natriuretic peptide (NT-proBNP) level were measured. The mean dosage of azilsartan was 30 ± 10 mg/day at baseline and that of sacubitril/valsartan after 3 months of treatment was 204 ± 64 mg/day. After 3 months, significant reductions in mean morning home BP (155 ± 17/80 ± 12 to 147 ± 16/76 ± 11 mmHg), mean nighttime home systolic BP (153 ± 19 to 144 ± 16 mmHg), and median (IQRs) NT-proBNP level [8124 (2620-13 394) to 6271 (1570-9591) pg/mL] were observed (all P < .05), whereas BP values during hemodialysis did not change significantly. In hemodialysis patients, except for hypotension, sacubitril/valsartan was generally well tolerated, effectively controlled out-of-office BP, and improved NT-proBNP.
Topics: Humans; Male; Aged; Hypertension; Tetrazoles; Valsartan; Aminobutyrates; Biphenyl Compounds; Angiotensin Receptor Antagonists; Drug Combinations; Heart Failure; Stroke Volume
PubMed: 36722379
DOI: 10.1111/jch.14635 -
JAMA Nov 2021There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial.
IMPORTANCE
There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%).
OBJECTIVE
To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%.
DESIGN, SETTING, AND PARTICIPANTS
A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019).
INTERVENTIONS
Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor.
MAIN OUTCOMES AND MEASURES
Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks.
RESULTS
Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%).
CONCLUSIONS AND RELEVANCE
Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03066804.
Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Biomarkers; Biphenyl Compounds; Double-Blind Method; Drug Combinations; Exercise Tolerance; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Quality of Life; Stroke Volume; Valsartan; Walk Test
PubMed: 34783839
DOI: 10.1001/jama.2021.18463 -
Molecules (Basel, Switzerland) May 2021Selenium-containing compounds are gaining more and more interest due to their valuable and promising pharmacological properties, mainly as anticancer and antioxidant...
Selenium-containing compounds are gaining more and more interest due to their valuable and promising pharmacological properties, mainly as anticancer and antioxidant agents. Ebselen, the up to now only approved drugs, is well known to possess very good glutathione peroxidase mimicking effects. To date, the most of efforts have been directed to build pure synthetic Se containing molecules, while less attention have been devoted to Se-based semisynthetic products resembling natural compounds like terpenes, polyphenols, and alkaloids. The aim of this short communication is to report the synthesis of the first example of a Se-phenylpropanoids, namely selenoauraptene, containing a selenogeranyl side chain in position 7 of the umbelliferone core. The key step was the Newman-Kwart rearrangement to obtain a selenocarbamate in which the Se atom was directly attached to umbelliferone (replacing its 7-OH function) followed by hydrolysis to get diumbelliferyl diselenide, which was finally easily converted to the desired Se-geranyl derivative in quite a good overall yield (28.5%). The synthesized adduct displayed a greater antioxidant and a radical scavenger in vitro activity than parent auraptene. The procedure we describe herein, to the best of our knowledge for the first time in the literature, represents an easy-to-handle method for the synthesis of a wide array of seleno analogues of naturally occurring biologically active oxyprenylated secondary metabolites.
Topics: Antioxidants; Benzothiazoles; Biphenyl Compounds; Coumarins; Picrates; Proton Magnetic Resonance Spectroscopy; Selenium Compounds; Sulfonic Acids
PubMed: 34068532
DOI: 10.3390/molecules26092798 -
Journal of the American College of... Jun 2021The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to... (Review)
Review
The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to "preserved" ejection fraction but referring to "below normal" ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the "mid range" may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with "reduced" (<40%), "mildly reduced," and "normal" (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Humans; Stroke Volume; Valsartan
PubMed: 34167646
DOI: 10.1016/j.jacc.2021.04.070 -
Journal of the American College of... Apr 2023Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse...
BACKGROUND
Some patients with heart failure may experience transient changes in kidney function upon transition to sacubitril/valsartan. Whether such changes portend adverse outcomes or influence long-term treatment benefits with sacubitril/valsartan continuation is unknown.
OBJECTIVES
This investigation aimed to evaluate the association between the occurrence of moderate estimated glomerular filtration rate (eGFR) decline (>15%) after initial exposure to sacubitril/valsartan and subsequent cardiovascular outcomes and its treatment benefits in PARADIGM-HF and PARAGON-HF.
METHODS
In sequential run-in phases, patients were titrated to enalapril 10 mg twice daily and then sacubitril/valsartan 97 mg/103 mg twice daily (in PARADIGM-HF) or valsartan 80 mg twice daily and then sacubitril/valsartan 49 mg/51 mg twice daily (in PARAGON-HF).
RESULTS
Among randomized participants, 11% in PARADIGM-HF and 10% in PARAGON-HF experienced eGFR decline (>15%) during sacubitril/valsartan run-in. eGFR partially recovered (from nadir to postrandomization week 16) regardless of sacubitril/valsartan continuation or switch to renin-angiotensin system inhibitor (RASi) postrandomization. Initial eGFR decline was not consistently associated with clinical outcomes in either trial. Treatment benefits of sacubitril/valsartan vs RASi on primary outcomes were similar irrespective of run-in eGFR decline in PARADIGM-HF (eGFR decline, HR: 0.69; 95% CI: 0.53-0.90; and no eGFR decline, HR: 0.80; 95% CI: 0.73-0.88; P = 0.32) and PARAGON-HF (eGFR decline, rate ratio [RR]: 0.84; 95% CI: 0.52-1.36 and no eGFR decline, RR: 0.87; 95% CI: 0.75-1.02, P = 0.92). The treatment effect of sacubitril/valsartan remained consistent across a range of eGFR declines.
CONCLUSIONS
Moderate eGFR decline when transitioning from RASi to sacubitril/valsartan is not consistently associated with adverse outcomes, and its long-term benefits are retained in heart failure across a broad range of eGFR declines. Early eGFR changes should not deter continuation of sacubitril/valsartan or stall uptitration. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitors with Angiotensin-Converting Enzyme Inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).
Topics: Humans; Tetrazoles; Angiotensin Receptor Antagonists; Stroke Volume; Treatment Outcome; Valsartan; Heart Failure; Aminobutyrates; Biphenyl Compounds; Drug Combinations; Enzyme Inhibitors; Kidney
PubMed: 36812948
DOI: 10.1016/j.jacc.2023.02.009 -
European Journal of Heart Failure Sep 2022We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425),... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat.
METHODS AND RESULTS
The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm.
CONCLUSIONS
Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov NCT02861534.
Topics: Aminobutyrates; Biphenyl Compounds; Drug Combinations; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Hyperkalemia; Hypotension; Pyrimidines; Stroke Volume; Treatment Outcome; Valsartan; Ventricular Dysfunction, Left
PubMed: 35791083
DOI: 10.1002/ejhf.2608 -
Molecules (Basel, Switzerland) May 2019There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from , which is widely used in...
There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from , which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.
Topics: Animals; Antidepressive Agents; Autonomic Nervous System; Biphenyl Compounds; Brain; Calcium; Cytokines; Depression; Disease Models, Animal; Hindlimb Suspension; Immobilization; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation Mediators; Kynurenine; Lignans; Lipopolysaccharides; Mice, Inbred ICR; NF-kappa B; RNA, Messenger; Swimming; Tryptophan
PubMed: 31141940
DOI: 10.3390/molecules24112035