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neprilysin - Top 30 Publications

Paradigm shift from diagnosing patients based on common symptoms to categorizing patients into subtypes with different pathogenic mechanisms to guide treatment for Alzheimer's disease.

Alzheimer's disease (AD) is a major cause of dementia in the elderly, and the number of AD patients is rapidly growing as life expectancy increases. However, disease-modifying drugs are not yet available. According to the amyloid hypothesis, disease onset is triggered by aggregation and accumulation of amyloid-β peptide, followed by formation of neurofibrillary tangles composed of hyperphosphorylated tau, and synaptic loss/neuronal cell death leading to dementia. Based on this hypothesis, various clinical trials for treatment of AD have been conducted, but most were discontinued due to failure to achieve cognitive improvement or appearance of adverse effects. Here we discuss the reasons for the failure of these trials. We suggest that biomarkers of specific, distinct molecular mechanisms of amyloidogenesis should be developed concomitantly with disease-modifying drugs (so-called companion diagnosis) to aid the proper design of clinical trials, as well as to enable personalized treatment of individual AD patients.

Efficacy and safety of crystalline valsartan/sacubitril (LCZ696) compared to placebo and combinations of free valsartan and sacubitril in patients with systolic hypertension: the RATIO study.

We compared the systolic blood pressure-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or co-administered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) in order to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office systolic BP 150-179 mmHg). Primary dependent variable was change in office systolic BP from baseline to week 8. At entry (n=907), mean age was 61.5 years, sitting office blood pressure (BP) 160/90.2 mmHg, and mean 24-hour ambulatory blood pressure 142/82.1 mmHg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory systolic BP with LCZ696 400mg than with valsartan 320mg (-5.7 and -3.4 mmHg, respectively, p<0.05 each). The systolic BP reduction with LCZ696 400 daily was similar to co-administered free valsartan 320mg and sacubitril 200mg. Effects were similar in those above and below age 65 and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily: 1) is superior to valsartan 320 mg daily for lowering systolic BP, 2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, 3) represents the optimal dosage for systolic hypertension in patients of any age, and 4) is safe and well tolerated.

Systemic administration of sialorphin attenuates experimental colitis in mice via interaction with mu and kappa opioid receptors.

Pharmacological treatment and/or maintenance of remission in inflammatory bowel disease (IBD) is currently one of the biggest challenges in the field of gastroenterology. Here we aimed to assess the anti-inflammatory effect and the mechanism of action of sialorphin, the natural blocker of the endogenous opioid peptide-degrading enzymes neprilysin (NEP) and aminopeptidase N (APN), in the mouse models of IBD and the changes in the expression of these enzymes in IBD patients.

Hypertension up to date: SPRINT to SPYRAL.

Hypertension is the most common chronic cardiovascular condition with increasing prevalence all over the world. Treatment of patients at risk requires a multimodal therapeutic concept to adjust blood pressure, including systematic identification of secondary causes of hypertension or pseudo-resistance, lifestyle modification, polypharmacy, and as well as accompanying risk factors and comorbidities. The present review discusses recent studies on patients with increased cardiovascular risk potentially influencing future treatment strategies. It covers blood pressure targets in patients at risk (SPRINT), novel treatment options such as angiotensin receptor neprilysin inhibitors, discusses the treatment of patients with impaired glucose tolerance, and appreciates novelties in controlling therapy-resistant hypertension by fourth-line pharmacotherapies (PATHWAY), as well as new interventional approaches.

Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.

Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.

Analysis of salivary protease spectrum in chronic periodontitis.

This study aimed to investigate the difference in salivary protease expression in patients with chronic periodontitis and normal individuals.

Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides.

The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.

Degradation paradigm of the Gut Hormone, Pancreatic Polypeptide, by hepatic and renal peptidases.

Pancreatic polypeptide (PP) is a gut hormone that acts on Y4 receptors to reduce appetite. Obese humans display a reduced postprandial rise in PP and remain fully sensitive to the anorectic effects of exogenous PP. The utility of PP as an antiobesity treatment is limited by its short circulating half-life. Insight into the mechanisms by which PP is degraded may aid design of long-acting PP analogues.We aimed to investigate the role of peptidases in PP degradation with a view to determining whether inhibition of these enzymes enhanced PP plasma levels and bioactivity in vivo. DPPIV and neprilysin (NEP) were two peptidase found to cleave PP. Limiting the effect of both peptidases improved the in vivo anorectic effect of PP and PP-based analogues. These studies suggest that inhibiting the degradation of PP using specific inhibitors and/or the design of analogues resistant to cleavage by DPPIV and NEP may be useful in the development of PP as an anti-obesity pharmacotherapy.

Angiotensin receptor neprilysin inhibitor treatment is safe and potentially efficacious in end‑stage hypertrophic cardiomyopathy.

Major developments in the 2016 european guidelines for heart failure.

The European Society of Cardiology has recently published new guidelines on the diagnosis and treatment of acute and chronic heart failure (HF). This article aims to review these recommendations and their level of scientific evidence and to present the most innovative aspects. The most significant deviations from the 2012 edition are: 1) the introduction of the concept of HF with midrange LVEF (40-49%); 2) a new diagnostic algorithm for chronic HF, initially considering the clinical probability; 3) recommendations on preventing or delaying the apparition of HF; 4) indications for the use of the new sacubitril-valsartan compound, the first angiotensin receptor blocker and neprilysin inhibitor; 5) modification of indications for cardiac resynchronisation therapy; and 6) a new algorithm for a combined diagnostic and treatment strategy for acute HF based on the presence or absence of congestion and hypoperfusion.

The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey.

Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p=0.026), Aβ1-40 (35.2%; p=0.04) and Aβtotal (29.8%; p=0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC(0-24h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p=0.039) and day 15 (34.7%; p=0.0003) and in shorter forms Aβ1-40 (23.4%; p=0.009), Aβ1-38 (64.1%; p=0.0001) and Aβtotal (50.45%; p=0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.

The association of MME microRNA Binding Site Polymorphism with risk of late onset Alzheimer's Disease in Northern Han Chinese.

Background Although amyloid β (Aβ) degradation has been normally implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cellular biological studies, genetic studies linking Aβ degradation and LOAD are still not deeply investigated. Neprilysin (NEP), as one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidases which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert posttranscriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs). Objective To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population. Method We screened a locus (rs6665) in 3' UTR of NEP gene (MME) sequence which was specially regulated by miRNA-187 , and further investigate its possible associations with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese. Results The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 acted as the significant risk associated with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035-1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found as the risk in ApoE ε4 carriers in LOAD (P=0.002, OR=1.846, 95%CI=1.264-2.697) was found. Conclusion Our study firstly confirmed the association of MME miRNA binding site polymorphism with risk of LOAD. However, the absolute association of MME with LOAD still requires more investigation.

A Breakthrough in the Treatment of Patients With Heart Failure With Reduced Ejection Fraction: the Clinical Significance of the PARADIGM HF-Trial.

The implementation into clinical practice of new therapeutic strategies that could improve the prognosis of patients with heart failure (HF) with reduced ejection fraction (HFrEF) remains relevant. Innovative approach is to restore imbalances of neurohumoral systems by inhibiting angiotensin II receptor and neprilysin. The review presents the role of the natriuretic peptides system in the HFrEF pathophysiology, historical approaches to neurohormonal modulation, clinical pharmacology of the first in the class of angiotensin receptor and neprilysin inhibitor sakubitril/valsartan. The results of the study PARADIGM-HF, in which sakubitril/valsartan therapy in patients with HFrEF compared with the recommended doses of enalapril was associated with the decrease of the of cardiovascular death and hospitalizations for HF by 20%, the risk of death from any cause by 16%, improvement of symptoms and exercise tolerance. Sakubitril/valsartan tolerated better than enalapril, rarely causes a cough, hyperkalemia or renal dysfunction. There was no increase in the risk of angioedema. Based on the results of the study PARADIGM-HF sakubitril/valsartan was included in the national and international guidelines for HF.

Expression of neprilysin in periodontitis-affected gingival tissues.

Although the pathogeneses of Alzheimer's disease (AD) and periodontal diseases have overlapping features, including ageing and chronic inflammation, the association between AD and periodontitis remains unclear. To explore the pathogenesis of periodontitis, a comprehensive gene expression/transcriptome analysis in periodontitis-affected gingival tissues found that the AD pathway was significantly up-regulated in periodontitis-affected gingival tissues. AD-related genes, amyloid beta precursor protein (APP), interleukin-1 beta and compliment 1QA, were significantly elevated in periodontitis. In the present study, balance between mRNA expression of APP and a potent amyloid degradation enzyme, neprilysin (NEP), as well as protein localisation of APP and NEP were analysed.

Sacubitril/Valsartan: The Newest Addition to the Toolbox for Guideline Directed Medical Therapy of Heart Failure.

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrade biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides resulting in natriuretic, diuretic, and vasodilatory effects. In patients chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and HF hospitalization compared to enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin converting enzyme inhibitors, angiotensin receptor blockers or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested cost-effectiveness of this new therapy. To assure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with several renal impairment, moderate hepatic impairment and low blood pressure and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema.

Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity.

The 24-residue peptide humanin (HN) has been proposed as peptide-based inhibitors able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

Indications and Clinical Implications of the Use of the Cardiac Markers BNP and NT-proBNP.

B-type natriuretic peptides are markers of myocardial wall stress. BNP or NT-proBNP are used for the differential diagnosis of acute dyspnoe where normal serum concentrations make a cardiac cause unlikely. New data show their importance for risk prediction in different stages of heart failure and in primary prevention. Natriuretic peptide guided therapy improves titration of heart failure medications. Compared to BNP, NT-proBNP is better suited during therapy with the new angiotensin-rezeptor-neprilysin-inhibitor Sacubitril/Valsartan. This review article summarizes current data on the importance of B-type natriuretic peptides for the interface of ambulatory and hospital care and presents recommendations for their practical use in patient care.

Potential Expanded Indications for Neprilysin Inhibitors.

The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease.

Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling.

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts.

Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1.5-fold higher than that in healthy people, thus causing a 1.5-fold increase in Aβ production. However, when comparing the causal relationship of Aβ accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aβ production alone. In this study, we found that neprilysin, a major Aβ-degrading enzyme, was downregulated in DS patient-derived fibroblasts, compared with healthy people-derived fibroblasts. Treatment with harmine, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is located in the DS critical region of chromosome 21, and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. These results suggest that a decrease in the Aβ catabolic rate may be, at least in part, one of the causes for accelerated AD-like pathogenesis in DS patients if a similar event occurs in the brains, and that neprilysin activity may be regulated directly or indirectly by DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.

Is there a place for a dual angiotensin receptor-neprilysin inhibitor in the treatment of hypertension?

What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan?

The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice.

Neprilysin facilitates adipogenesis through potentiation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway.

Neprilysin (NEP) is a zinc metallopeptidase that cleaves a number of small peptides into inactive forms. Despite the recent evidence of a significant correlation between the levels of NEP in plasma and the severity of obesity in humans, a cause-and-effect relationship or a functional role of NEP in obesity has remained uncertain. In this study, we show that NEP has a positive regulatory effect on fat cell formation from precursor cells. NEP increases the accumulation of cytoplasmic triglycerides in 3T3-L1 preadipocytes or the C3H10T1/2 mesenchymal stem cell line in differentiation conditions. Consistently, cells expressing NEP showed an increase in mRNA expression of adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and the adipocyte markers aP2 and adipsin. Furthermore, this NEP-enhanced induction of adipogenesis was found to require the enzymatic activity of NEP, leading to augmentation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. In summary, our results indicate that NEP accelerates adipogenesis through enhancement of insulin-mediated PI3K-Akt activation and imply a high therapeutic value of NEP in treating obesity and obesity-related disorders.

Clinical features and prognosis in CD10(-) pre-B acute lymphoblastic leukemia.

Objective: To analyze the clinical features and prognosis of acute lymphoblastic leukemia patients with immunophenotype of CD10(-)pre-B (CD10(-) pre B-ALL) . Methods: 6 adult cases with CD10(-) pre B-ALL immunophenotypes were analyzed retrospectively, related literatures were reviewed to clarify these kind of patients' clinical features and prognosis. Results: CD10(-) pre B-ALL occurred in 1.5% of ALL, 1.8% of B-ALL and 11.5% of pre B-ALL respectively. All the 6 patients were male with the median age as 33.5 years old, the median white blood cells was 101.78×10(9)/L, MLL-AF4 fusion transcripts were evident in all cases. Complete remission (CR) was achieved in 5 patients after first induction chemotherapy, 1 patient failed to respond to induction therapy, and got CR after 3 courses of chemotherapy. 2 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR(1), 1 patient relapsed in the short term and underwent allo-HSCT in CR(2). 1 patient was still waiting for allo-HSCT. Of the 2 patients who didn't receive transplantation, 1 died following a relapse, the other remained to be in CR. Conclusions: CD10(-) pre B-ALL was a rare but distinct subtype in adult ALL characterized by male dominance, high onset white blood cells and MLL rearrangement rate. Conventional chemotherapy produced a high response rate but more likely relapse, allo-HSCT may have the potential to improve the prognosis of these patients.

Trichoblastic carcinoma of the scalp with rippled pattern.

Trichoblastic carcinoma (TC) is a rare type of malignancy which is derived from the hair follicles. In this paper, we report a case with TC on the scalp characterized with rippled pattern. There have been reports of rippled pattern in trichoblastomas, sebaceomas, and basal cell carcinomas. To the best of our knowledge, this is the first case in the literature to report a rippled pattern in TCs.

Identification of prognostic factors in patients with diffuse large B-cell lymphoma.

To identify prognostic factors for patients with diffuse large B-cell lymphoma (DLBCL), specifically those classified into conflicting subgroups by Hans' and Choi's classification algorithms. We retrospectively reviewed clinical and pathological data of 154 patients diagnosed with de novo DLBCL in the First Hospital of Jilin University from January 2004 to September 2011. All cases were classified into subgroups based on Hans' and Choi's algorithms with immunohistochemical markers.

Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer's disease mouse model: possible involvement of the cholinergic system.

Sporadic Alzheimer's disease (SAD) is a slowly progressive neurological disorder that is the most common form of dementia. Cholinergic system dysfunction and amyloid beta formation are the two main underlying pathological mechanisms for the disease development. In recent studies, insulin receptor desensitization and disturbances in the downstream effects of insulin receptor signaling were observed in the brains of Alzheimer's patients. Currently, intracereberoventricular (ICV) injection of streptozotocin (STZ) is found to induce behavioral, neurochemical, and structural alterations in animals resembling those found in SAD patients. Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was recently shown to regulate the transcription of several genes in both in vivo and in vitro models of Alzheimer's disease. The aim of the current study is to investigate the potential effect of different doses of valproic acid, in an ICV-STZ-induced animal model of SAD. Streptozotocin-injected mice showed cognitive and spatial memory dysfunction in the Y-maze, object recognition test, and Morris water maze (MWM) neurobehavioral tests. The mice also exhibited a decrease in acetylcholine (ACh) and neprilysin (NEP) levels accompanied by an increase in acetylcholinesterase (AChE) activity. For the first time to our knowledge, our findings have shown that VPA is capable of restoring ACh levels in ICV-STZ-injected mice, as well as normalizing both NEP levels and AChE activity. Via this mechanism, an enhancement of cognitive functions is observed. Thus, VPA is suggested to be a promising therapeutic approach against SAD.

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer's disease.

Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD.Cell Death and Differentiation advance online publication, 10 February 2017; doi:10.1038/cdd.2016.161.

Neprilysin Inhibitors in Cardiovascular Disease.

Mortality from heart failure remains high despite advances in medical therapy over the last three decades. Angiotensin receptor-neprilysin inhibitor (ARNI) combinations are the latest addition to the heart failure medical armamentarium, which is built on the cornerstone regimen of beta blockers, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and aldosterone antagonists. Recent trial data have shown a significant mortality benefit from ARNIs, which, as of May 2016, have now received a class I recommendation for use in patients with heart failure and reduced ejection fraction from the major American and European cardiology societies.

Resolution of Cheyne-Stokes Respiration after Treatment of Heart Failure with Sacubitril/Valsartan: A First Case Report.

Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF), and is known to be associated with a worse prognosis. The severity of central sleep apnea is thought to mirror cardiac dysfunction. The novel angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril has been shown to improve HF, but a relationship between treatment with ARNi and the severity of SDB has not yet been investigated. We report the case of a 71-year-old male with HF and SDB. Treatment with sacubitril/valsartan was associated with improved cardiac function, as shown by a reduction in the level of N-terminal prohormone of brain natriuretic peptide from 3,249 to 1,720 pg/mL, and an improvement in left-ventricular ejection fraction from 30 to 35%. This was accompanied by a marked reduction in the apnea-hypopnea index (from 41 to 19/h). To the best of our knowledge, this is the first case to document parallel improvements in HF and SDB after the initiation of ARNi treatment.