A Diet Containing Rutin Ameliorates Brain Intracellular Redox Homeostasis in a Mouse Model of Alzheimer's Disease.

Quercetin has been studied extensively for its anti-Alzheimer's disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and rutin on intracellular redox homeostasis of the brain (reduced glutathione/oxidized glutathione, GSH/GSSG), its correlation with ß-site APP cleaving enzyme 1 (BACE1) activity, and amyloid precursor protein (APP) expression in transgenic TgAPP mice (bearing human Swedish mutation APP transgene, APPswe). On the basis that BACE1 protein and APP processing are regulated by the ubiquitin-proteasome pathway and that supplementation with GSH protects neurons from proteasome inhibition, we investigated whether a diet containing quercetin or rutin (30 mg/kg/day, 4 weeks) diminishes several early signs of AD. Genotyping analyses of animals were carried out by PCR. In order to determine intracellular redox homeostasis, spectrofluorometric methods were adopted to quantify GSH and GSSG levels using o-phthalaldehyde and the GSH/GSSG ratio was ascertained. Levels of TBARS were determined as a marker of lipid peroxidation. Enzyme activities of SOD, CAT, GR, and GPx were determined in the cortex and hippocampus. ΒACE1 activity was measured by a secretase-specific substrate conjugated to two reporter molecules (EDANS and DABCYL). Gene expression of the main antioxidant enzymes: APP, BACE1, a Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), caspase-3, caspase-6, and inflammatory cytokines were determined by RT-PCR. First, overexpression of APPswe in TgAPP mice decreased GSH/GSSG ratio, increased malonaldehyde (MDA) levels, and, overall, decreased the main antioxidant enzyme activities in comparison to wild-type (WT) mice. Treatment of TgAPP mice with quercetin or rutin increased GSH/GSSG, diminished MDA levels, and favored the enzyme antioxidant capacity, particularly with rutin. Secondly, both APP expression and BACE1 activity were diminished with quercetin or rutin in TgAPP mice. Regarding ADAM10, it tended to increase in TgAPP mice with rutin treatment. As for caspase-3 expression, TgAPP displayed an increase which was the opposite with rutin. Finally, the increase in expression of the inflammatory markers IL-1ß and IFN-γ in TgAPP mice was lowered by both quercetin and rutin. Collectively, these findings suggest that, of the two flavonoids, rutin may be included in a day-to-day diet as a form of adjuvant therapy in AD.

A Neuroprotective Bovine Colostrum Attenuates Apoptosis in Dexamethasone-Treated MC3T3-E1 Osteoblastic Cells.

Glucocorticoid-induced osteoporosis (GIO) is one of the most common secondary forms of osteoporosis. GIO is partially due to the apoptosis of osteoblasts and osteocytes. In addition, high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, induces neurodegeneration by initiating inflammatory processes leading to neural apoptosis. Here, a neuroprotective bovine colostrum against glucocorticoid-induced neuronal damage was investigated for its anti-apoptotic activity in glucocorticoid-treated MC3T3-E1 osteoblastic cells. A model of apoptotic osteoblastic cells was developed by exposing MC3T3-E1 cells to DEX (0-700 µM). Colostrum co-treated with DEX was executed at 0.1-5.0 mg/mL. Cell viability was measured for all treatment schedules. Caspase-3 activation was assessed to determine both osteoblast apoptosis under DEX exposure and its potential prevention by colostrum co-treatment. Glutathione reduced (GSH) was measured to determine whether DEX-mediated oxidative stress-driven apoptosis is alleviated by colostrum co-treatment. Western blot was performed to determine the levels of p-ERK1/2, Bcl-XL, Bax, and Hsp70 proteins upon DEX or DEX plus colostrum exposure. Colostrum prevented the decrease in cell viability and the increase in caspase-3 activation and oxidative stress caused by DEX exposure. Cells, upon colostrum co-treated with DEX, exhibited higher levels of p-ERK1/2 and lower levels of Bcl-XL, Bax, and Hsp70. Our data support the notion that colostrum may be able to reduce DEX-induced apoptosis possibly via the activation of the ERK pathway and modulation of the Hsp70 system. We provided preliminary evidence on how bovine colostrum, as a complex and multi-component dairy product, in addition to its neuroprotective action, may affect osteoblastic cell survival undergoing apoptosis.

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation.

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer's disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, ß-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.

Peripheral IL-6 Levels but not Sarcopenia Are Predictive of 1-Year Mortality After Hip Fracture in Older Patients.

BACKGROUND: Sarcopenic patients may have an increased risk of poor outcomes after a hip fracture. The objective of this study was to determine whether sarcopenia and a set of biomarkers were potential predictors of 1-year-mortality in older patients after a hip fracture. METHODS: About 150 patients at least 80 years old were hospitalized for the surgical treatment of a hip fracture. The primary outcome measure was the death in the first year after the hip fracture. Sarcopenia was defined at baseline by having both low muscle mass (bioimpedance analysis) and handgrip and using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) definition of probable sarcopenia. Janssen's (J) and Masanés (M) cutoff points were used to define low muscle mass. RESULTS: Mortality 1 year after the hip fracture was 11.5%. In univariate analyses, baseline sarcopenia was not associated with mortality, using neither of the muscle mass cutoff points: 5.9% in sarcopenic (J) versus 12.4% in non-sarcopenic participants (p = .694) and 16% in sarcopenic (M) versus 9.6% in non-sarcopenic participants (p = .285). Probable sarcopenia (EWGSOP2) was not associated with mortality. Peripheral levels of IL-6 at baseline were significantly higher in the group of participants who died in the year after the hip fracture (17.14 ± 16.74 vs 11.42 ± 7.99 pg/mL, p = .026). TNF-α peripheral levels had a nonsignificant trend to be higher in participants who died. No other biomarker was associated with mortality. CONCLUSIONS: Sarcopenia at baseline was not a predictor of 1-year mortality in older patients after a hip fracture. IL-6 was associated with a higher risk of mortality in these patients, regardless of sarcopenia status.

Medication reconciliation upon admission in paediatric hospital setting: preliminary data.

Background The benefits of medication reconciliation are well established in adult patients, but not in paediatric patients, being a population not included in the guidelines for medication reconciliation published so far. However, it is known that a significant number of children suffer from chronic illnesses leading to a complex pharmacological treatment. Moreover, there are a series of specific factors that cause a greater risk of medication errors in children. Aim The purpose of the present study was to determine whether patients from a paediatric hospital setting may benefit from medication reconciliation at hospital admission, in order to prevent and reduce prescribing errors on admission. Main outcome measures The primary outcome was the number of discrepancies between best possible medication history and prescribed treatment upon admission and, consequently, number of reconciliation errors. The secondary outcome was the main underlying disease with the highest number of reconciliation errors, and the main pharmacotherapeutic groups involved. Results The pharmacist reconciled the medication of 187 patients with an mean age of 6.6 ± 5.1 years. Sixty percent of patients had a base disease and 12.3% had polypharmacy, with an average of 6 drugs per patient. In a 42% of patients, at least one discrepancy was detected between their home treatment and the prescribed treatment upon admission, with 15% of patients having at least one reconciliation error (68% omissions). Neurological diseases were the main underlying disease with at least one reconciliation error (50%). The main pharmacotherapeutic groups involved in reconciliation errors were psychoanaleptic and psycholeptic, anti-acids, antiepileptic, and obstructive airway pharmacotherapy; each accounting for a 17.1%, 14.7%, 11.8% and 11.8% of the total, respectively. Conclusion Within our sample of paediatric patients, the rate of medication discrepancy and reconciliation errors at hospital admission was as relevant in terms of pharmacotherapy as has been reported in adults. The most frequent type of errors was omission of some home treatments. The main underlying disease with at least one error was neurological. As a whole, the detection of reconciliation errors in paediatrics by provision of medication reconciliation could be effective in reducing medication errors.

Biomarkers of sarcopenia in very old patients with hip fracture.

BACKGROUND: Hip fracture is both a cause and a consequence of sarcopenia. Older persons with sarcopenia have an increased risk of falling, and the prevalence of sarcopenia may be increased in those who suffer a hip fracture. The aim of this study was to explore potential biomarkers (neuromuscular and peripheral pro-inflammatory and oxidative stress markers) that may be associated with sarcopenia in very old persons with hip fracture. METHODS: We recruited 150 consecutive patients ≥80 years old admitted to an orthogeriatric unit for an osteoporotic hip fracture. Muscle mass was assessed pre-operatively using bioelectrical impedance analysis; Janssen's (J) and Masanés' (M) reference cut-off points were used to define low muscle mass. Muscle strength was assessed with handgrip strength (Jamar's dynamometer). Sarcopenia was defined by having both low muscle mass and strength and using the European Working Group on Sarcopenia in Older People 2 definition of probable sarcopenia (low grip strength). Peripheral markers-pro-inflammatory and oxidative stress parameters-were determined either in the plasma or in the erythrocyte fraction obtained from peripheral whole blood of every patient pre-operatively. RESULTS: Mean age was 87.6 ± 4.9 years, and 78.7% were women. The prevalence of sarcopenia was 11.5% with Janssen's, 34.9% with Masanés' cut-offs, and 93.3% with the European Working Group on Sarcopenia in Older People 2 definition of probable sarcopenia. Among the four pro-inflammatory cytokines tested in plasma, only tumour necrosis factor-α was different (lower) in sarcopenic than in non-sarcopenic participants using both muscle mass cut-offs (J 7.9 ± 6.2 vs. 8.3 ± 5.8, M 6.8 ± 4.7 vs. 9.1 ± 6.2). Erythrocyte glutathione system showed a non-significant tendency to lower glutathione levels and glutathione/oxidized glutathione ratios in sarcopenic participants compared with non-sarcopenic subjects. Catalase activity was also lower in sarcopenic participants (J 2904 ± 1429 vs. 3329 ± 1483, M 3037 ± 1430 vs. 3431 ± 1498). No significant differences were found between groups in chymotrypsin-like activity of the 20S proteasome, superoxide dismutase, glutathione peroxidase and butyrylcholinesterase activity, C-terminal agrin fragment, interferon-γ, or interleukin-1ß. CONCLUSIONS: The prevalence of sarcopenia in patients with hip fracture varies according to the definition and the muscle mass reference cut-off points used. We did not find differences in most neuromuscular, pro-inflammatory, or oxidative stress markers, except for lower peripheral tumour necrosis factor-α levels and catalase activity in sarcopenic participants, which may be markers of an early inflammatory reaction that is hampered in sarcopenic patients.

Several targets involved in Alzheimer's disease amyloidogenesis are affected by morin and isoquercitrin.

Long-term consumption of phytochemicals has been associated with a decreased risk of dementia. The modes of action of two flavonols (morin and isoquercitrin) and two flavanones (hesperidin and neohesperidin) were characterized as single-compound drugs in several Alzheimer's disease (AD)-related assays. First, these phytochemicals were assayed in an amyloid toxicity model (MC65 cells). Second, we examined the activity of the flavonoids in cell-free assays against ß- and γ-secretases and acetylcholinesterase activities, as well as agents able to modify the fibrillogenesis of the amyloid ß-peptide. Additionally, they were assayed against glutamate-induced oxytosis, as scavengers of reactive oxygen species (ROS), as inhibitors of caspase-3, -8 and -9 activation and as modulators of the chymotrypsin-like activity of the ubiquitin-proteasome system. Morin and isoquercitrin, unlike flavanones, exhibited significant activities as ß- and γ-secretase inhibitors, as well as capacity to inhibit Aß aggregation and favor its disaggregation. Flavonols and flavanones showed ROS scavenger activity (P < 0.05), attenuation of caspase-3 and -9 activation (P < 0.05) and restoration of the reduced chymotrypsin-like activity of proteasome 20S (P < 0.05) upon H2O2 exposure of APPswe cells. Flavanones failed to protect against glutamate-induced oxytosis. These findings provide new insight into the anti-amyloidogenic effects of morin and isoquercitrin.

Fall-risk increasing drugs and recurrent injurious falls association in older patients after hip fracture: a cohort study protocol.

Polypharmacy and fall-risk increasing drugs (FRIDS) have been associated with injurious falls. However, no information is available about the association between FRIDS and injurious falls after hospital discharge due to hip fracture in a very old population. We aim to assess the association between the use of FRIDS at discharge and injurious falls in patients older than 80 years hospitalized due to a hip fracture. A retrospective cohort study using routinely collected health data will be conducted at the Orthogeriatric Unit of a teaching hospital. Patients will be included at hospital discharge (2014), with a 2-year follow-up. Fall-risk increasing drugs will be recorded at hospital discharge, and exposure to drugs will be estimated from usage records during the 2-year follow-up. Injurious falls are defined as falls that lead to any kind of health care (primary or specialized care, including emergency department visits and hospital admissions). A sample size of 193 participants was calculated, assuming that 40% of patients who receive any FRID at discharge, and 20% who do not, will experience an injurious fall during follow up. This protocol explains the study methods and the planned analysis. We expect to find a relevant association between FRIDS at hospital discharge and the incidence of injurious falls in this very old, high risk population. If confirmed, this would support the need for a careful pharmacotherapeutic review in patients discharged after a hip fracture. However, results should be carefully interpreted due to the risk of bias inherent to the study design.

Prevalencia de sarcopenia y características de los sarcopénicos en pacientes mayores de 80 años ingresados por fractura de cadera / Prevalence of sarcopenia and characteristics of sarcopenic subjects in patients over 80 years with hip fracture

Objetivo: calcular la prevalencia de sarcopenia en ancianos ingresados por fractura de cadera (FC) y comparar las características de sarcopénicos y no sarcopénicos. Método: se incluyeron 150 pacientes consecutivos de 80 o más años ingresados por una FC. Se diagnosticó sarcopenia a aquellos con baja masa muscular (bioimpedanciometría, puntos de corte de Janssen y Masanés) y baja fuerza muscular (dinamómetro de Jamar). Se recogieron variables sociodemográficas, cognitivas (Pfeiffer, GDS-Reisberg), funcionales (Barthel, FAC), nutricionales (MNA-SF, índice de masa corporal [IMC], ángulo de fase) y se registró el número de caídas y el número de fármacos. Resultados: edad media: 87,6 ± 4,9 años (78,7% mujeres). La prevalencia de sarcopenia fue del 11,5% (Janssen) y 34,9% (Masanés). Del 77,5% que deambulaba de forma independiente, un 40% había sufrido ≥ 3 caídas. El 38% padecía demencia. Un 80,4% presentaba dependencia leve-moderada y el 14,2% era independiente para actividades básicas de la vida diaria (ABVD). El MNA era compatible con malnutrición en el 12,6% y tomaba ≥ 4 medicamentos el 85,2%. Los pacientes sarcopénicos (Masanés) presentaban índice de masa corporal más bajo (18,6 vs. 24,3, p = 0,003); no se encontraron diferencias entre sarcopénicos y no sarcopénicos en otras variables. No hubo asociación entre el ángulo de fase y la sarcopenia. Conclusiones: hasta un tercio de los pacientes mayores que ingresaron por FC presentan sarcopenia en el momento del ingreso. La prevalencia, en el presente estudio, depende de los puntos de corte usados para definir la baja masa muscular. En contra de lo previsible, los pacientes sarcopénicos con FC muy mayores apenas se diferencian de los no sarcopénicos, salvo por un menor IMC

Aim: to estimate the prevalence of sarcopenia in very old patients admitted to an Orthogeriatric Unit for the treatment of a hip fracture (HF), and to compare characteristics of patients with and without sarcopenia. Methods: one hundred and fifty consecutive patients ≥ 80 years old admitted with HF were included. Sarcopenia was diagnosed with low muscle mass (bioimpedance, using two different cut-off points, Janssen and Masanés) and low grip strength (Jamar's dynamometer). Socio-demographic, nutritional variables (MNA-SF, body mass index [BMI], phase angle), cognitive (Pfeiffer, Reisberg's GDS) and functional variables (Barthel index, FAC) were registered, as well as the number of recent falls and medications on admission. Results: mean age: 87.6 ± 4.9 years (78.7% women). Prevalence of sarcopenia: 11.5% (Janssen's cut-offs) and 34.9% (Masanés cut-offs). Of the 77.5% who had independent ambulation before the fracture, 40% reported three or more recent falls. Before admission, 38% had dementia and 80.4% had mild to moderate dependence to BADL before admission; 14.2% were independent for all BADL. MNA was suggestive of malnutrition in 12.6%, and 85.2% were on four or more prescribed drugs. Sarcopenic (Masanés) had a lower BMI than non-sarcopenic participants (18.6 vs 24.3, p = 0.003), but no other significant differences were found between both groups. Phase angle was also unrelated to sarcopenia status. Conclusions: up to one third of very old patients with HF had sarcopenia on admission. Prevalence varied widely depending on the cut-off points selected to define low muscle mass. Sarcopenic patients in this setting were mostly similar to non-sarcopenic patients, except for a lower BMI

[Prevalence of sarcopenia and characteristics of sarcopenic subjects in patients over 80 years with hip fracture]. / Prevalencia de sarcopenia y características de los sarcopénicos en pacientes mayores de 80 años ingresados por fractura de cadera.

INTRODUCTION: Aim: to estimate the prevalence of sarcopenia in very old patients admitted to an Orthogeriatric Unit for the treatment of a hip fracture (HF), and to compare characteristics of patients with and without sarcopenia. Methods: one hundred and fifty consecutive patients ≥ 80 years old admitted with HF were included. Sarcopenia was diagnosed with low muscle mass (bioimpedance, using two different cut-off points, Janssen and Masanés) and low grip strength (Jamar's dynamometer). Socio-demographic, nutritional variables (MNA-SF, body mass index [BMI], phase angle), cognitive (Pfeiffer, Reisberg's GDS) and functional variables (Barthel index, FAC) were registered, as well as the number of recent falls and medications on admission. Results: mean age: 87.6 ± 4.9 years (78.7% women). Prevalence of sarcopenia: 11.5% (Janssen's cut-offs) and 34.9% (Masanés cut-offs). Of the 77.5% who had independent ambulation before the fracture, 40% reported three or more recent falls. Before admission, 38% had dementia and 80.4% had mild to moderate dependence to BADL before admission; 14.2% were independent for all BADL. MNA was suggestive of malnutrition in 12.6%, and 85.2% were on four or more prescribed drugs. Sarcopenic (Masanés) had a lower BMI than non-sarcopenic participants (18.6 vs 24.3, p = 0.003), but no other significant differences were found between both groups. Phase angle was also unrelated to sarcopenia status. Conclusions: up to one third of very old patients with HF had sarcopenia on admission. Prevalence varied widely depending on the cut-off points selected to define low muscle mass. Sarcopenic patients in this setting were mostly similar to non-sarcopenic patients, except for a lower BMI.

INTRODUCCIÓN: Objetivo: calcular la prevalencia de sarcopenia en ancianos ingresados por fractura de cadera (FC) y comparar las características de sarcopénicos y no sarcopénicos. Método: se incluyeron 150 pacientes consecutivos de 80 o más años ingresados por una FC. Se diagnosticó sarcopenia a aquellos con baja masa muscular (bioimpedanciometría, puntos de corte de Janssen y Masanés) y baja fuerza muscular (dinamómetro de Jamar). Se recogieron variables sociodemográficas, cognitivas (Pfeiffer, GDS-Reisberg), funcionales (Barthel, FAC), nutricionales (MNA-SF, índice de masa corporal [IMC], ángulo de fase) y se registró el número de caídas y el número de fármacos. Resultados: edad media: 87,6 ± 4,9 años (78,7% mujeres). La prevalencia de sarcopenia fue del 11,5% (Janssen) y 34,9% (Masanés). Del 77,5% que deambulaba de forma independiente, un 40% había sufrido ≥ 3 caídas. El 38% padecía demencia. Un 80,4% presentaba dependencia leve-moderada y el 14,2% era independiente para actividades básicas de la vida diaria (ABVD). El MNA era compatible con malnutrición en el 12,6% y tomaba ≥ 4 medicamentos el 85,2%. Los pacientes sarcopénicos (Masanés) presentaban índice de masa corporal más bajo (18,6 vs. 24,3, p = 0,003); no se encontraron diferencias entre sarcopénicos y no sarcopénicos en otras variables. No hubo asociación entre el ángulo de fase y la sarcopenia. Conclusiones: hasta un tercio de los pacientes mayores que ingresaron por FC presentan sarcopenia en el momento del ingreso. La prevalencia, en el presente estudio, depende de los puntos de corte usados para definir la baja masa muscular. En contra de lo previsible, los pacientes sarcopénicos con FC muy mayores apenas se diferencian de los no sarcopénicos, salvo por un menor IMC.

Fall-risk increasing drugs and prevalence of polypharmacy in older patients discharged from an Orthogeriatric Unit after a hip fracture.

BACKGROUND: Polypharmacy and fall-risk increasing drugs (FRIDS) have been associated with injurious falls. We aimed to estimate the prevalence of polypharmacy and FRIDS in older patients discharged from an Orthogeriatric Unit after a hip fracture surgery. METHODS: This study describes the baseline findings of a 2-year retrospective cohort study. We included patients older than 80 years discharged from an Orthogeriatric Unit who were able to walk before surgery. Patient's baseline variables, total number of drugs, and FRIDS at hospital discharge were collected. RESULTS: We included 228 patients. The mean number of drugs and FRIDS prescribed at discharge was 11.6 ± 3.0 and 2.9 ± 1.6, respectively. Polypharmacy was prevalent in all patients except in three: 23.3% (5-9 drugs) and 75.9% (≥ 10 drugs). Only 11 patients had no FRIDS and 35.5% were on > 3 FRIDS. The most prevalent FRIDS were: agents acting on the renin-angiotensin system (43.9%) and anxiolytics (39.9%). The number of FRIDS was higher in patients with extreme polypharmacy (3.4 ± 1.5) than in those on 5-9 drugs (1.5 ± 1.0, p < 0.05). Independent people in performing instrumental activities had lower risk of extreme polypharmacy (≥ 10 drugs) or > 3 FRIDS: OR 0.39 (95% CI 0.18-0.83) and OR 0.41 (95% CI 0.20-0.84), respectively. People living in a nursing home had higher risk of > 3 FRIDS: OR 4.03 (95% CI 1.12-14.53). CONCLUSIONS: Polypharmacy and fall-risk increasing drugs are prevalent in patients discharged from orthogeriatric care after surgery for a hip fracture. Interventions on drug use at hospital discharge could have a potential impact on falls in this high-risk population.

Prevalence and determinants of self-medication practice among selected households in Addis Ababa community.

BACKGROUND AND AIM: Self-medication (SM) is one part of self-care which is known to contribute to primary health care. If practiced appropriately, it has major benefits for the consumers such as self-reliance and decreased expense. However, inappropriate practice can have potential dangers such as incorrect self-diagnosis, dangerous drug-drug interactions, incorrect manner of administration, incorrect dosage, incorrect choice of therapy, masking of a severe disease, and/or risk of dependence and abuse. The main objective of this study was to assess the prevalence and determinants of the self-medication practice (SMP) in Addis Ababa. METHODOLOGY: A community based cross-sectional study was conducted among selected households in Addis Ababa from April 2016 to May 2016, with a recall period of two months before its conduction. Trained data collectors were employed to collect the data from the 604 sampled participants using pre-tested and validated questionnaires. RESULT: Among the 604 participants involved in this study, 422 (69.9%) were female and 182 (30.1%) were male and there was a mean age of 41.04 (± 13.45) years. The prevalence of SM in this study was 75.5%. The three most frequently reported ailments were headache 117 (25.7%), abdominal pain 59 (12.9%) and cough 54 (11.8%). The two main reasons for SM were mildness of illness 216 (47.4%) and previous knowledge about the drug 106 (23.2%). The two most frequently consumed medications were paracetamol 92 (20.2%) and traditional remedies 73 (16.0%), while drug retail outlets 319 (83.3%) were the main source of drugs. The two most frequently reported source of drug information were health professionals 174 (45.4%) and experience from previous treatment 82 (21.4%). Moreover, there were statistically significant differences among respondents who reported practicing SM based on income and knowledge about appropriate SMP. CONCLUSION AND RECOMMENDATION: Self-medication was practiced with a range of drugs from the conventional paracetamol and NSAIDs to antimicrobials. Being that the practice of SM is inevitable, health authorities and professionals are highly demanded to educate the public not only on the advantages and disadvantages of SM but on its proper use.

Neurohormetic responses of quercetin and rutin in a cell line over-expressing the amyloid precursor protein (APPswe cells).

BACKGROUND: Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulation of signaling pathways which are responsible for its neuroprotective effects. PURPOSE: We attempt to explore the molecular mechanisms involved in the neurohormetic responses to quercetin and rutin exposure, in a SH-SY5Y cell line which stably overexpresses the amyloid precursor protein (APP) Swedish mutation, based on a biphasic concentration-response relationship for cell viability. METHODS: We examined the impact of both natural compounds, at concentrations in its hormetic range on the following cell parameters: chymotrypsin-like activity of the proteasome system; PARP-1 protein levels and expression and caspase activation; APP processing; and the main endogenous antioxidant enzymes. RESULTS: Proteasome activities following quercetin or rutin treatment were significantly augmented in comparison with non-treated cells. Activity of caspase-3 was significantly attenuated by treatment with quercetin or rutin. Modest increased levels of PARP-1 protein and mRNA transcripts were observed in relation to the mild increase of proteasome activity. Significant reductions of the full-length APP and sAPP protein and APP mRNA levels were related to significant enhancements of α-secretase ADAM-10 protein and mRNA transcripts and significant increases of BACE processing in cells exposed to rutin. Furthermore, quercetin or rutin treatment displayed an overall increase of the four antioxidant enzymes. CONCLUSIONS: The upregulation of the proteasome activity observed upon quercetin or rutin treatment could be afforded by a mild increased of PARP-1. Consequently, targeting the proteasome by quercetin or rutin to enhance its activity in a mild manner could avoid caspase activation. Moreover, it is likely that APP processing of cells upon rutin treatment is mostly driven by the non-amyloidogenic pathway leading to a putative reduction of ßA production. Overall induction of endogenous antioxidant enzymes under quercetin or rutin treatments of APPswe cells might modulate its proteasome activity. We might conclude that quercetin and rutin might exert a neurohormetic cell response affecting various signaling pathways and molecular networks associated with modulation of proteasome function.

Age-dependent effects of esculetin on mood-related behavior and cognition from stressed mice are associated with restoring brain antioxidant status.

Dietary antioxidants might exert an important role in the aging process by relieving oxidative damage, a likely cause of age-associated brain dysfunctions. This study aims to investigate the influence of esculetin (6,7-dihydroxycoumarin), a naturally occurring antioxidant in the diet, on mood-related behaviors and cognitive function and its relation with age and brain oxidative damage. Behavioral tests were employed in 11-, 17- and 22-month-old male C57BL/6J mice upon an oral 35day-esculetin treatment (25mg/kg). Activity of antioxidant enzymes, GSH and GSSG levels, GSH/GSSG ratio, and mitochondrial function were analyzed in brain cortex at the end of treatment in order to assess the oxidative status related to mouse behavior. Esculetin treatment attenuated the increased immobility time and enhanced the diminished climbing time in the forced swim task elicited by acute restraint stress (ARS) in the 11- and 17-month-old mice versus their counterpart controls. Furthermore, ARS caused an impairment of contextual memory in the step-through passive avoidance both in mature adult and aged mice which was partially reversed by esculetin only in the 11-month-old mice. Esculetin was effective to prevent the ARS-induced oxidative stress mostly in mature adult mice by restoring antioxidant enzyme activities, augmenting the GSH/GSSG ratio and increasing cytochrome c oxidase (COX) activity in cortex. Modulation of the mood-related behavior and cognitive function upon esculetin treatment in a mouse model of ARS depends on age and is partly due to the enhancement of redox status and levels of COX activity in cortex.

In vivo [¹8F] FDG PET imaging reveals that p-chloroamphetamine neurotoxicity is associated with long-term cortical and hippocampal hypometabolism.

PURPOSE: p-Chloroamphetamine (PCA) is a neurotoxin that selectively degenerates the serotonin (5-HT) axon terminals. In order to study the brain metabolic consequences induced by serotonergic denervation, a single dose of PCA (2.5 or 10 mg/kg i.p.) was administered to male adult rats. PROCEDURES: In vivo regional brain metabolism was evaluated 3 and 21 days after PCA (2.5 or 10 mg/kg; i.p.) injection by 2-deoxy-2-[(18)F] fluoro-D-glucose ([(18)F] FDG) positron emission tomography (PET). At day 22, the following markers of neurotoxicity were determined: (a) 5-HT axon terminal lesion by 5-HT transporter (SERT) autoradiography, (b) reactive gliosis by glial fibrillary acidic protein immunohistochemistry, and (c) eventual neurodegeneration by DAPI/Fluoro-Jade C labeling. RESULTS: An average of 20 % reduction of [(18)F] FDG uptake in most brain areas was observed at day 21 under 10 mg/kg PCA treatment. Instead, 2.5 mg/kg PCA only reduced metabolic activity in neocortex. Likewise, the high dose of PCA exerted a strong decrease (>30 %) in SERT density in several 5-HT innervated regions, but no effect was found in midbrain raphe nuclei, the main source of serotonergic neurons. Although PCA induced astroglial activation both in hippocampus and cortex in response to axotomy, no signs of neuronal death in these areas were detected. CONCLUSIONS: Overall, [(18)F] FDG PET revealed that the reduction of the brain metabolic activity induced by PCA is related to 5-HT axon terminal lesion, with no apparent affectation of neuronal viability.

Processing of the platelet amyloid precursor protein in the mild cognitive impairment (MCI).

It has been suggested that mild cognitive impairment (MCI) patients deteriorate faster than the healthy elderly population and have an increased risk of developing dementia. Certain blood molecular biomarkers have been identified as prognostic markers in Alzheimer's disease (AD). The present study was aimed to assess the status of the platelet amyloid precursor protein (APP) metabolism in MCI and AD subjects and establish to what extent any variation could have a prognostic value suggestive of predictive AD in MCI patients. Thirty-four subjects diagnosed with MCI and 45 subjects with AD were compared to 28 healthy elderly individuals for assessing for protein levels of APP, ß-APP cleaving enzyme 1 (BACE1), presenilin 1 (PS1) and a disintegrin and metalloproteinase-10 (ADAM-10) by western blot, and for the enzyme activities of BACE1 and γ-secretase by using specific fluorogenic substrates, in samples of platelets. A similar pattern in the healthy elderly and MCI patients was found for BACE1 and PS1 levels. A reduction of APP levels in MCI and AD patients compared with healthy elderly individuals was found. Augmented levels of ADAM-10 in both MCI and AD were displayed in comparison with age-matched control subjects. The ratio ADAM-10/BACE1 was higher for the MCI group versus AD group. Whereas BACE1 and PS1 levels were only increased in AD regarding to controls, BACE1 and γ-secretase activities augmented significantly in both MCI and AD groups. Finally, differences and similarities between MCI and AD patients were observed in several markers of platelet APP processing. Larger sample sets from diverse populations need to be analyzed to define a signature for the presence of MCI or AD pathology and to early detect AD at the MCI stage.

Discovery of alkenylboronic acids as neuroprotective agents affecting multiple biological targets involved in Alzheimer's disease.

Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the ß-amyloid (ßA) aggregation process, ß-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.

SNP-mediated neuroprotection under glucose deprivation is enhanced by Hypericum perforatum.

Hypericum perforatum is a medicinal herb possessing ability for protecting neurons from oxidative stress. Since nitric oxide (NO) may be protective against oxidative stress-induced cell death as occurs in glucose deprivation (GD)-induced neurotoxicity, whether a standardized extract of H. perforatum (HP) increases the NO-mediated neuroprotective effect in GD-PC12 cells was investigated. Induced death in PC12 cells by GD exposure for 18 h was partially prevented by cell incubation with sodium nitroprusside (SNP), a NO-donor. SNP increased survival and nitrite production in GD-cells in a concentration-dependent manner. Co-incubation of cells with 10 µM SNP plus 50-100 µg/ml HP under GD insult significantly prevented GD-induced cell death to a higher extent than SNP alone as shown by an augmentation of cell survival and intracellular bcl-2 levels and a decrease of lipid peroxidation, caspase-3 activation and PARP cleavage. Cytoprotection by the NO-donor was almost abolished by the use of a NO scavenger and potentiated by the presence of superoxide dismutase. SNP and/or HP neuroprotection on GD-cells was significantly reversed by rotenone treatment. These results suggest that: (1) SNP could protect PC12 cells from GD-induced cytotoxicity through NO generation and (2) the enhancement of the SNP-mediated neuroprotective effect on GD-cells by HP might arise in part through scavenging of reactive oxygen species (ROS) and inhibition of mitochondrial dysfunction associated with the hypoglycemic episode. This current finding might highlight the development of therapeutic strategies aimed at manipulating NO-donors in combination with herb supplements containing ROS scavenger compounds for prophylaxis from brain ischemia.

Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells.

AIMS: Quercetin and rutin have been reported to exert numerous pharmacological activities, such as free-radical scavenging, effects on immune and inflammatory cell functions, and could have benefits in Alzheimer's disease (AD) by mitigating cellular damage induced by reactive oxygen species (ROS). A key event in AD is the conversion of the ß-amyloid (Aß) peptide into amyloid plaques in the brain. Preventing Aß aggregation is pursued as a therapeutic strategy for treating AD. In this study, antiamyloidogenic and antioxidant properties of quercetin and rutin were investigated. MAIN METHODS: We investigated whether quercetin and rutin affect Aß25-35 fibrillogenesis, BACE activity and the cellular redox status. KEY FINDINGS: Quercetin and rutin inhibited the formation of Aß fibrils and disaggregated Aß fibrils. ß-secretase enzyme (BACE) activity was significantly inhibited by rutin. To resemble the in vivo Aß-induced neurotoxicity we used a cell system overexpressing APP Swedish mutation (APPswe), which is associated with early-onset familial AD, and may promote oxidative stress due to the enhanced Aß production. Quercetin and rutin decreased almost completely ROS generation in H(2)O(2)-treated APPswe cells. Both flavonoids increased intracellular GSH content and the redox status, and for rutin this effect was concentration dependent. Besides, quercetin and rutin diminished the index of lipid peroxidation in comparison with control APPswe cells at all concentrations tested. SIGNIFICANCE: Our findings may provide an explanation of the neuroprotective effect of quercetin and rutin, suggesting that they could be dietary phytochemicals able to revert the ß-amyloid toxicity in vivo.

Synthesis and evaluation of arylquinones as BACE1 inhibitors, ß-amyloid peptide aggregation inhibitors, and destabilizers of preformed ß-amyloid fibrils.

BACE1 activity, inhibition of Aß aggregation, and disaggregation of preformed Aß fibrils constitute the three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alzheimer's disease (AD). Quinones are widely distributed among natural products and possess relevant and varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase, antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing. Our studies put forward that these compounds are promising candidates in the development of new drugs which are effective simultaneously towards the three major targets of AD.