Novel role of the nutraceutical bioactive compound berberine in lectin-like OxLDL receptor 1-mediated endothelial dysfunction in comparison to lovastatin.

BACKGROUND AND AIMS: Oxidized LDL (oxLDL) or pro-inflammatory stimuli lead to increased oxidative stress linked to endothelial dysfunction and atherosclerosis. The oxLDL receptor-1 (LOX1) is elevated within atheromas and cholesterol-lowering statins inhibit LOX1 expression. Berberine (BBR), an alkaloid extracted from plants of gender Berberis, has lipid-lowering and anti-inflammatory activity. However, its role in regulating LOX1-mediated signaling is still unknown. The aim of this study was to investigate the effect of BBR on oxLDL- and TNFα-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs) and to compare it with that of lovastatin (LOVA). METHODS AND RESULTS: Cytotoxicity was determined by lactate dehydrogenase assay. Antioxidant capacity was measured with chemiluminescent and fluorescent method and intracellular ROS levels through a fluorescent dye. Gene and protein expression levels were assayed by qRT-PCR and western blot, respectively. HUVECs exposure to oxLDL (30 µg/ml) or TNFα (10 ng/ml) for 24 h led to a significant increase in LOX1 expression, effect abrogated by BBR (5 µM) and LOVA (5 µM). BBR but not LOVA treatment abolished the TNFα-induced cytotoxicity and restored the activation of Akt signaling. In spite of a low direct antioxidant capacity, both compounds reduced intracellular ROS levels generated by treatment of TNFα but only BBR inhibited NOX2 expression, MAPK/Erk1/2 signaling and subsequent NF-κB target genes VCAM and ICAM expression, induced by TNFα. CONCLUSIONS: These findings demonstrated for the first time that BBR could prevent the oxLDL and TNFα - induced LOX1 expression and oxidative stress, key events that lead to NOX, MAPK/Erk1/2 and NF-κB activation linked to endothelial dysfunction. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Berberine (PubChem CID: 2353); Lovastatin (PubChem CID: 53232).

Underprescription of medications in older adults: causes, consequences and solutions-a narrative review.

PURPOSE: Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it. METHODS: A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies. RESULTS: Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription. CONCLUSION: Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.

Dietary antioxidants as potential pharmacological agents for ischemic stroke.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Heart rate reduction with ivabradine in the early phase of atherosclerosis is protective in the endothelium of ApoE-deficient mice.

Ivabradine, a heart rate reducing agent, protects the vascular system by unidentified mechanisms. We sought to determine the effects of the treatment with ivabradine, started before plaque formation, on early transcriptional changes and endothelium lesions in regions of aorta subjected to disturbed blood flow. Six week-old apolipoprotein E-deficient (ApoE-/-) mice, fed a low-fat diet, were treated with ivabradine to determine the effect on transcriptional changes (2-and 4-week treatment) and on lesions formation (19-week treatment) in the endothelium of the aortic arch. Microarrays analysis (60k probes) of endothelium-enriched RNA was carried out to detect changes in gene expression induced by treatment. Endothelium damage was assessed by en-face immunofluorescence staining for vascular endothelial (VE) cadherin. According to microarray analysis, 930 transcripts were affected by the treatment. We found downregulation of pro-apoptotic and pro-inflammatory genes, the majority of which are nuclear factor-κB (NF-κB)-and/or angiotensin II-regulated genes, and upregulation of anti-inflammatory genes. Many shear stress-responsive genes were affected by the treatment and the MAPK, Notch signalling and sterol metabolic processes were among the most significantly affected pathways. Consistently, we observed increased levels of Hes5, a Notch target gene, together with a reduction of endothelium damage, in the lower aortic arch of treated- compared with untreated- mice. We concluded that an early treatment with ivabradine protected the endothelium of the aortic arch of ApoE-/- mice. Activation of the Notch signalling could be part of the mechanism underlying this protection.

Diagnosing and treating depression in older and oldest old.

Depression is very common in older people and it is associated with negative consequences such as functional decline, increased morbidity and mortality and higher healthcare costs. Despite this, it is still underdiagnosed and undertreated and the issue is particularly relevant for people older than 80 years. The main reasons for underdiagnosis are: atypical presentation, concomitant cognitive decline, inadequate diagnostic tools, and prejudice that depression is a normal part of ageing. On the other hand, the main reasons for undertreatment are: multimorbidity, concerns about adverse events and drug interactions, lack of confidence in the efficacy and safety of pharmacological and non-pharmacological treatments in the oldest old depressed patients, who are underrepresented in clinical studies. The new antidepressants are the drugs most frequently used, due to their perceived more favorable safety profile than older antidepressants. Psychotherapy is equally effective but less frequently used and should request some adaptive strategies for the peculiarities of octogenarians. Electroconvulsive therapy is limited to severe psychotic late-life depression resistant to other treatments. In light of the heterogeneity of people aged 80 years and over, with multiple and different medical, functional, socioeconomic problems, a multidimensional approach is probably the most suitable both for diagnosis and treatment, in order to develop an individualized care plan. These considerations should guide the formulation of future research studies, specifically tailored for the oldest depressed patients.

[IFN in the treatment of chronic viral hepatitis. Efficacy and tolerance of lymphoblastoid alpha interferon in HIV-negative drug addicts and associated chronic active hepatitis C]. / IFN nel trattamento dell'epatite virale cronica. Efficacia e tollerabilità dell'alfa IFN linfoblastoide in pazienti tossicodipendenti HIV negativi, affetti da ECA HCV correlata.

The authors evaluated the efficacy and tolerance of low dose lymphoblastoid alpha interferon in 14 i.v. drug addicts with histologically confirmed chronic active hepatitis C. Patients were treated for 12 months; all completed the whole treatment without complaining of significant side effects. Four months after withdrawal of treatment, 13 patients were found to be in clinical and biohumoral remission with serum transaminases within the normal range already after 12 weeks.

Alteration of Notch signaling and functionality of adipose tissue derived mesenchymal stem cells in heart failure.

AIM: Circulating mesenchymal cells increase in heart failure (HF) patients and could be used therapeutically. Our aim was to investigate whether HF affects adipose tissue derived mesenchymal cell (adMSC) isolation, functional characteristics and Notch pathway. METHODS AND RESULTS: We compared 25 patients with different degrees of HF (11 NYHA classes I and II and 14 NYHA III and IV) with 10 age and gender matched controls. 100% adMSC cultures were obtained from controls, while only 72.7% and 35.7% from patients with mild or severe HF (p<0.0001). adMSC from HF patients showed higher markers of senescence (p16 positive cells: 14±2.3% in controls and 35.6±5.6% (p<0.05) and 69±14.7% (p<0.01) in mild or severe HF; γ-H2AX positive cells: 3.7±1.2%, 19.4±4.1% (p<0.05) and 23.7±3.4% (p<0.05) respectively), lower proliferation index (Ki67 positive cells: 21.5±4.9%, 13.2±2.8% and 13.7±3.2%, respectively), reduced pluripotency-associated genes (Oct4 positive cells: 86.7±4.9%, 55±12% (p<0.05) and 43.3±8.7% (p<0.05), respectively; NANOG positive cells: 89.8±3.7%, 39.6±14.4% (p<0.01) and 47±8.1%, respectively), and decreased differentiation markers (α-sarcomeric actin positive cells: 79.8±4.6%, 49±18.1% and 47±12.1% (p<0.05) and CD31-positive endothelial cells: 24.5±2.9%, 0.5±0.5% (p<0.001) and 2.3±2.3% (p<0.001), respectively). AdMSC from HF patients also showed reduced Notch transcriptional activity (lowered expression of Hey 1 and Hey 2 mRNAs). Stimulation with TNF-α of adMSC isolated from controls affected the transcription of several components of the Notch pathway (reduction of Notch 4 and Hes 1 mRNAs and increase of Notch 2 and Hey 1 mRNAs). CONCLUSIONS: In HF yield and functionality of adMSC are impaired and their Notch signaling is downregulated.

Health care for older people in Italy: The U.L.I.S.S.E. Project (Un link informatico sui servizi sanitari esistenti per l'anziano - a computerized network on health care services for older people).

OBJECTIVES: The U.L.I.S.S.E. study is aimed at describing older patients who are cared for in hospitals, home care or nursing homes in Italy. DESIGN: The U.L.I.S.S.E. study is an observational multicenter prospective 1-year study. SETTING: Overall, 23 acute geriatric or internal medicine hospital units, 11 home care services and 31 nursing homes participated in the study. MEASUREMENTS: The patient's evaluation was performed using comprehensive geriatric assessment instruments, i.e. the interRAI Minimum Data Set, while data on service characteristics were recorded using ad-hoc designed questionnaires. RESULTS: The older subjects who are in need of acute and long term care in Italy have similar characteristics: their mean age is higher than 80 years, they have a high level of disability in ADL, an important multimorbidity, and are treated with several drugs. The prevalence of cognitive impairment is particularly high in nursing homes, where almost 70% of residents suffer from it and 40% have severe cognitive impairment. On the other hand, there is a shortage of health care services, which are heterogeneous and fragmented. CONCLUSIONS: Health care services for older people in Italy are currently inadequate to manage the complexity of the older patients. An important effort should be undertaken to create a more integrated health care system.

Validation of the Italian version of the falls efficacy scale international (FES-I) and the short FES-I in community-dwelling older persons.

Fear of falling (FF) is a common problem in older persons. FF negatively affects the quality of life by generating anxiety, loss of confidence and of self-efficacy, and, ultimately, activity restriction and increased risk of falling. The FES-I and Short FES-I are two instruments developed to assess FF in older persons which have been already validated in some European countries. Our objectives are to develop the Italian version of FES-I and the Short FES-I and to validate them in older persons. The back translation protocol adopted by the ProFaNE group was used to translate both scales from English to Italian. Participants were 157 community-dwelling persons aged>65 years who underwent comprehensive geriatric assessment, including a structured interview concerning FF, and were administered the FES-I and the Short FES-I. Both scales were re-tested after 4 weeks in 151 persons. FES-I and Short FES-I had high internal validity and test-retest reliability. The Short FES-I is highly comparable with the FES-I. We conclude that the FES-I and the Short FES-I are excellent instruments to asses FF in Italian older subjects and they may be used in future research projects and clinical trials.