The role of nutrient-based epigenetic changes in buffering against stress, aging, and Alzheimer's disease.

Converging evidence identifies stress-related disorders as putative risk factors for Alzheimer Disease (AD). This article reviews evidence on the complex interplay of stress, aging, and genes-epigenetics interactions. The recent classification of AD into preclinical, mild cognitive impairment, and AD offers a window for intervention to prevent, delay, or modify the course of AD. Evidence in support of the cognitive effects of epigenetics-diet, and nutraceuticals is reviewed. A proactive epigenetics diet and nutraceuticals program holds promise as potential buffer against the negative impact of aging and stress responses on cognition, and can optimize vascular, metabolic, and brain health in the community.

Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia.

Introduction. Converging evidence suggests that PDE-4 (phosphodiesterase subtype 4) plays a crucial role in regulating cognition via the PDE-4-cAMP cascade signaling involving phosphorylated cAMP response element binding protein (CREB). Objective. The primary endpoint was to examine the neurocognitive effects of extract Sceletium tortuosum (Zembrin) and to assess the safety and tolerability of Zembrin in cognitively healthy control subjects. Method. We chose the randomized double-blind placebo-controlled cross-over design in our study. We randomized normal healthy subjects (total n = 21) to receive either 25 mg capsule Zembrin or placebo capsule once daily for 3 weeks, in a randomized placebo-controlled 3-week cross-over design. We administered battery of neuropsychological tests: CNS Vital Signs and Hamilton depression rating scale (HAM-D) at baseline and regular intervals and monitored side effects with treatment emergent adverse events scale. Results. 21 subjects (mean age: 54.6 years ± 6.0 yrs; male/female ratio: 9/12) entered the study. Zembrin at 25 mg daily dosage significantly improved cognitive set flexibility (P < 0.032) and executive function (P < 0.022), compared with the placebo group. Positive changes in mood and sleep were found. Zembrin was well tolerated. Conclusion. The promising cognitive enhancing effects of Zembrin likely implicate the PDE-4-cAMP-CREB cascade, a novel drug target in the potential treatment of early Alzheimer's dementia. This trial is registered with ClinicalTrials.gov NCT01805518.

Liposomal-formulated curcumin [Lipocurc™] targeting HDAC (histone deacetylase) prevents apoptosis and improves motor deficits in Park 7 (DJ-1)-knockout rat model of Parkinson's disease: implications for epigenetics-based nanotechnology-driven drug platform.

BACKGROUND: Converging evidence suggests dysregulation of epigenetics in terms of histone-mediated acetylation/deacetylation imbalance in Parkinson's disease (PD). Targeting histone deacetylase (HDAC) in neuronal survival and neuroprotection may be beneficial in the treatment and prevention of neurodegenerative disorders. Few pharmacological studies use the transgenic model of PD to characterize the neuroprotection actions of a lead compound known to target HDAC in the brain. METHODS: In our study, we investigated neuroprotective effects of liposomal-formulated curcumin: Lipocurc™ targeting HDAC inhibitor in the DJ-1(Park 7)-gene knockout rat model of PD. Group I (DJ-1-KO-Lipocurc™) received Lipocurc™ 20 mg/kg iv 3× weekly for 8 weeks; Group II: DJ-1 KO controls (DJ-1 KO-PBS) received i.v. phosphate-buffered saline (PBS). Group III: DJ-1-Wild Type (DJ-1 WT-PBS) received PBS. We monitored various components of motor behavior, rotarod, dyskinesia, and open-field behaviors, both at baseline and at regular intervals. Toward the end of the 8 weeks, we measured neuronal apoptosis and dopamine (DA) neuron-specific tyrosine hydroxylase levels by immunohistochemistry methods at post-mortem. RESULTS: We found that DJ-KO Group I and Group II, as compared with DJ-1 WT group, exhibited moderate degree of motor impairment on the rotarod test. Lipocurc™ treatment improved the motor behavior motor impairment to a greater extent than the PBS treatment. There was marked apoptosis in the DJ-1 WT group. Lipocurc™ significantly blocked neuronal apoptosis: the apoptotic index of DJ-1-KO-Lipocurc™ group was markedly reduced compared with the DJ-KO-PBS group (3.3 vs 25.0, p<0.001). We found preliminary evidence Lipocurc™ stimulated DA neurons in the substantia nigra. The ratio of immature to mature DA neurons in substantia nigra was statistically higher in the DJ-1-KO-Lipocurc™ group (p<0.025). CONCLUSIONS: We demonstrated for the first time Lipocurc™'s anti-apoptotic and neurotrophic effects in theDJ-1-KO rat model of PD. Our promising findings warrant randomized controlled trial of Lipocurc™ in translating the novel nanotechnology-based epigenetics-driven drug discovery platform toward efficacious therapeutics in PD.

Televaluation and usability assessment of the human-machine interface for a novel adaptive health knowledge translation system.

We describe results from usability assessment of a novel adaptive health knowledge translation system interface. Search or retrieval logic, navigation, and presentation elements are crucial to delivering best content. Design requirements have been enhanced by assessing participant needs and desired features.

Sensitivity to cholecystokinin-tetrapeptide in major depression.

BACKGROUND: Sensitivity to the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) is enhanced in panic disorder patients relative to normal controls (NC). In the present study, we determined whether sensitivity to CCK-4 is enhanced in patients with major depressive disorder (MDD) with no history of panic attacks. We also determined whether CCK-4 would exacerbate depressive symptoms. METHODS: The study used a double-blind, randomized, placebo-controlled design. Behavioral and cardiovascular response to a submaximal dose (20 microg) of CCK-4 was studied in seven patients with MDD and 12 NC subjects. RESULTS: None of the subjects panicked with placebo, whereas 29% of MDD and 17% of NC subjects panicked with CCK-4. There was no significant difference between groups on the frequency of CCK-4-induced panic or the number and intensity of panic symptoms. No significant difference was detected for cardiovascular response to the CCK-4 challenge. CCK-4 did not worsen depressive symptoms in MDD patients. LIMITATIONS: Small number of study subjects. CONCLUSIONS: These data indicate that MDD patients show a response to CCK-4 that is comparable to NC. The lack of effect of CCK-4 on depressive symptoms suggest that central CCK receptors may not play an important role in the pathophysiology of MDD.