BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.

/pdf/flavonoids-an-overview-5gkev1wgy2.pdf

Flavonoids: an overview

BACKGROUND
After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation.


OBJECTIVE
To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia.


METHODS
Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs.


RESULTS
Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33).


CONCLUSION
The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

The prevention of dementia with antihypertensive treatment. New evidence from the systolic hypertension in europe (Syst-Eur) study☆

Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders.

/pdf/polyphenols-multipotent-therapeutic-agents-in-3g8dfd4lin.pdf

Polyphenols: multipotent therapeutic agents in neurodegenerative diseases.

Redox proteomics: chemical principles, methodological approaches and biological/biomedical promises.

Anatabine lowers Alzheimer's Aβ production in vitro and in vivo.

BACKGROUND: In addition to experiencing traumatic events while deployed in a combat environment, there are other factors that contribute to the development of posttraumatic stress disorder (PTSD) in military service members. This study explored the contribution of genetics, childhood environment, prior trauma, psychological, cognitive, and deployment factors to the development of traumatic stress following deployment. METHODS: Both pre- and postdeployment data on 231 of 458 soldiers were analyzed. Postdeployment assessments occurred within 30 days from returning stateside and included a battery of psychological health, medical history, and demographic questionnaires; neurocognitive tests; and blood serum for the D2 dopamine receptor (DRD2), apolipoprotein E (APOE), and brain-derived neurotropic factor (BDNF) genes. RESULTS: Soldiers who screened positive for traumatic stress at postdeployment had significantly higher scores in depression (d = 1.91), anxiety (d = 1.61), poor sleep quality (d = 0.92), postconcussion symptoms (d = 2.21), alcohol use (d = 0.63), traumatic life events (d = 0.42), and combat exposure (d = 0.91). BDNF Val66 Met genotype was significantly associated with risk for sustaining a mild traumatic brain injury (mTBI) and screening positive for traumatic stress. Predeployment traumatic stress, greater combat exposure and sustaining an mTBI while deployed, and the BDNF Met/Met genotype accounted for 22% of the variance of postdeployment PTSD scores (R (2) = 0.22, P CONCLUSION: These findings suggest predeployment traumatic stress, genetic, and environmental factors have unique contributions to the development of combat-related traumatic stress in military service members. Language: en

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/brb3.392

Brain-derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress.

Background

Evidence suggests that dihydropyridine calcium channel blockers may be useful in preventing and treating Alzheimer's disease (AD).



Objective

In an open-label trial of safety and tolerability of nilvadipine in patients with AD, we examined cognition and executive function over a short time period to determine an influence of nilvadipine on these outcomes.



Method

We investigated change in cognition using the Mini mental state examination and in executive function using the EXIT25 in 55 patients with AD who received nilvadipine 8 mg daily for 6 weeks compared with 30 non-treated subjects with AD. Apolipoprotein E genotyping was performed, and the study team and caregivers were kept blinded to APOE e4 status during the trial.



Results

Aside from differences in gender and education, both the treatment and the control groups were similar in general demographics and on baseline cognition status. After correction for potential confounders, APOE e4 status, and use of other antihypertensive medications, a significant impact of study intervention was observed on MMSE (F = 8.67, p < 0.01) and EXIT (F = 8.77, p < 0.03) scores. An interaction between APOE e4 carrier status and treatment (p ≤ 0.05) was observed for both outcome measures.



Conclusion

In this open-label trial, among APOE e4 non-carriers, we observed stabilization of cognition and improvement in executive function among treated individuals compared with non-treated individuals. Among APOE e4 carriers, cognitive stabilization was evident for treated individuals whereas a cognitive decline was observed in non-treated individuals. These findings provide additional evidence for potential therapeutic efficacy of nilvadipine in treating AD and warrant further investigation. Copyright © 2011 John Wiley & Sons, Ltd.

Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients--an open-label trial.

Alzheimer's disease (AD) is characterized by the brain accumulation of Aβ peptides and by the presence of neurofibrillary tangles. Aβ is believed to play an important role in AD and it has been shown that certain flavonoids can affect Aβ production. Recently, it was suggested that the Aβ lowering properties of flavonoids are mediated by a direct inhibition the β-secretase (BACE-1) activity, the rate limiting enzyme responsible for the production of Aβ peptides. Westernblots and ELISAs were employed to monitor the impact of flavonoids on amyloid precursor protein processing and Aβ production. A cell free chemoluminescent assay using human recombinant BACE-1 was used to assess the effect of flavonoids on BACE-1 activity. The effect of flavonoids on NFκB activation was determined by using a stable NFκB luciferase reporter cell line. Molecular docking simulations were performed to predict the binding of flavonoids to the BACE-1 catalytic site. Real time quantitative PCR was used to determine the effect of flavonoids on BACE-1 transcription. We show in a cell free assay that flavonoids are only weak inhibitors of BACE-1 activity. Docking simulation studies with different BACE-1 structures also suggest that flavonoids are poor BACE-1 inhibitors as they appear to adopt various docking poses in the active site pocket and have weak docking scores that differ as a function of the BACE-1 structures studied. Moreover, a weak correlation was observed between the effect of flavonoids on Aβ production in vitro and their ability to lower BACE-1 activity suggesting that the Aβ lowering properties of flavonoids in whole cells are not mediated via direct inhibition of BACE-1 activity. We found however a strong correlation between the inhibition of NFκB activation by flavonoids and their Aβ lowering properties suggesting that flavonoids inhibit Aβ production in whole cells via NFκB related mechanisms. As NFκB has been shown to regulate BACE-1 expression, we show that NFκB lowering flavonoids inhibit BACE-1 transcription in human neuronal SH-SY5Y cells. Altogether, our data suggest that flavonoids inhibit Aβ and sAPPβ production by regulating BACE-1 expression and not by directly inhibiting BACE-1 activity.

/pdf/flavonoids-lower-alzheimer-s-ab-production-via-an-nfkb-3ha8s4q2hu.pdf

Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Anatabine, a naturally occurring alkaloid, is becoming a commonly used human food supplement, taken for its claimed anti-inflammatory properties although this has not yet been reported in human clinical trials. We have previously shown that anatabine does display certain anti-inflammatory properties and readily crosses the blood-brain barrier suggesting it could represent an important compound for mitigating neuro-inflammatory conditions. The present study was designed to determine whether anatabine had beneficial effects on the development of experimental autoimmune encephalomyelitis (EAE) in mice and to precisely determine its underlying mechanism of action in this mouse model of multiple sclerosis (MS). We found that orally administered anatabine markedly suppressed neurological deficits associated with EAE. Analyses of cytokine production in the periphery of the animals revealed that anatabine significantly reduced Th1 and Th17 cytokines known to contribute to the development of EAE. Anatabine appears to significantly suppress STAT3 and p65 NFκB phosphorylation in the spleen and the brain of EAE mice. These two transcription factors regulate a large array of inflammatory genes including cytokines suggesting a mechanism by which anatabine antagonizes pro-inflammatory cytokine production. Additionally, we found that anatabine alleviated the infiltration of macrophages/microglia and astrogliosis and significantly prevented demyelination in the spinal cord of EAE mice. Altogether our data suggest that anatabine may be effective in the treatment of MS and should be piloted in clinical trials.

/pdf/amelioration-of-experimental-autoimmune-encephalomyelitis-by-wf64uwfraf.pdf

Venkat Mathura

Papers

Anatabine lowers Alzheimer's Aβ production in vitro and in vivo.

Brain-derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress.

Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients--an open-label trial.

Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism.

Amelioration of experimental autoimmune encephalomyelitis by anatabine.