SIRT1 Coordinates Transcriptional Regulation of Neural Activity and Modulates Depression-Like Behaviors in the Nucleus Accumbens.

BACKGROUND: Major depression and anxiety disorders are significant causes of disability and socioeconomic burden. Despite the prevalence and considerable impact of these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for these conditions. We evaluated the role of SIRT1 in regulating dysfunctional processes of reward by using chronic social defeat stress to induce depression- and anxiety-like behaviors. Chronic social defeat stress induces physiological and behavioral changes that recapitulate depression-like symptomatology and alters gene expression programs in the nucleus accumbens, but cell type-specific changes in this critical structure remain largely unknown. METHODS: We examined transcriptional profiles of D1-expressing medium spiny neurons (MSNs) lacking deacetylase activity of SIRT1 by RNA sequencing in a cell type-specific manner using the RiboTag line of mice. We analyzed differentially expressed genes using gene ontology tools including SynGO and EnrichR and further demonstrated functional changes in D1-MSN-specific SIRT1 knockout (KO) mice using electrophysiological and behavioral measurements. RESULTS: RNA sequencing revealed altered transcriptional profiles of D1-MSNs lacking functional SIRT1 and showed specific changes in synaptic genes including glutamatergic and GABAergic (gamma-aminobutyric acidergic) receptors in D1-MSNs. These molecular changes may be associated with decreased excitatory and increased inhibitory neural activity in Sirt1 KO D1-MSNs, accompanied by morphological changes. Moreover, the D1-MSN-specific Sirt1 KO mice exhibited proresilient changes in anxiety- and depression-like behaviors. CONCLUSIONS: SIRT1 coordinates excitatory and inhibitory synaptic genes to regulate the GABAergic output tone of D1-MSNs. These findings reveal a novel signaling pathway that has potential for the development of innovative treatments for affective disorders.

Phase I dose-escalation, safety, and CNS pharmacokinetic study of dexanabinol in patients with brain cancer.

BACKGROUND: Dexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose. METHODS: Dexanabinol formulated in cremophor/ethanol was administered once weekly via 3-hour intravenous infusion to patients with brain cancer. RESULTS: A total of 26 patients were dosed once weekly at 2, 4, 8, 16, 24, 28, and 36 mg/kg. Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment. A recommended phase II dose of dexanabinol was established at 28 mg/kg due to related, reversible adverse events at higher dose levels that required medications for symptomatic relief. The most common drug-related toxicities were the depressed level of consciousness and lightheadedness, diarrhea, itching, fatigue, chest discomfort, and tingling in the mouth. Systemic exposure to dexanabinol (AUC0-t and C max) increased from 2 to 36 mg/kg, with dose nonproportionality apparent at the highest dose; dexanabinol was present in appreciable levels in the cerebrospinal fluid (CSF), which implies the possibility of exposure of intracranial tumors to drug. Five of 24 efficacy-evaluable patients (21%) experienced stable disease with a median duration of 2 cycles (28-day cycle) as the best response. CONCLUSIONS: Dexanabinol administered weekly by intravenous infusion was safe and well-tolerated up to 28 mg/kg in brain cancer patients, but has limited antitumor activity in patients with brain cancer.

Predictive Modeling of a Batch Filter Mating Process.

Quantitative characterizations of horizontal gene transfer are needed to accurately describe gene transfer processes in natural and engineered systems. A number of approaches to the quantitative description of plasmid conjugation have appeared in the literature. In this study, we seek to extend that work, motivated by the question of whether a mathematical model can accurately predict growth and conjugation dynamics in a batch process. We used flow cytometry to make time-point observations of a filter-associated mating between two E. coli strains, and fit ordinary differential equation models to the data. A model comparison analysis identified the model formulation that is best supported by the data. Identifiability analysis revealed that the parameters were estimated with acceptable accuracy. The predictive power of the model was assessed by comparison with test data that demanded extrapolation from the training experiments. This study represents the first attempt to assess the quality of model predictions for plasmid conjugation. Our successful application of this approach lays a foundation for predictive modeling that can be used both in the study of natural plasmid transmission and in model-based design of engineering approaches that employ conjugation, such as plasmid-mediated bioaugmentation.

Effects of Dietary Strawberry Supplementation on Antioxidant Biomarkers in Obese Adults with Above Optimal Serum Lipids.

Berries have shown several cardiovascular health benefits and have been associated with antioxidant functions in experimental models. Clinical studies are limited. We examined the antioxidant effects of freeze-dried strawberries (FDS) in adults [n = 60; age: 49 ± 10 years; BMI: 36 ± 5 kg/m(2) (mean ± SD)] with abdominal adiposity and elevated serum lipids. Participants were randomized to one of the following arms: low dose strawberry (25 g/day FDS), low dose control beverage (LD-C), high dose strawberry (50 g/d FDS), and high dose control beverage (HD-C) for 12 weeks. Control beverages were matched for calories and total fiber. Plasma antioxidant capacity, trace elements (copper, iron, selenium, and zinc), whole blood glutathione (GSH), and enzyme activity (catalase, glutathione peroxidase, and glutathione reductase) were examined at screening (0 week) and after 12 weeks' intervention. At 12 weeks, plasma antioxidant capacity and glutathione levels were higher in the strawberry versus control groups (low and high dose FDS: 45% and 42% for plasma antioxidant capacity and 28% and 36% for glutathione, resp.); glutathione was higher in the high versus low dose strawberry group (all p < 0.05). Serum catalase activity was higher in the low dose strawberry (43%) versus control group (p < 0.01). No differences were noted in plasma trace elements and glutathione enzyme activity. Dietary strawberries may selectively increase plasma antioxidant biomarkers in obese adults with elevated lipids.

Freeze-dried strawberries lower serum cholesterol and lipid peroxidation in adults with abdominal adiposity and elevated serum lipids.

Dietary flavonoid intake, especially berry flavonoids, has been associated with reduced risks of cardiovascular disease (CVD) in large prospective cohorts. Few clinical studies have examined the effects of dietary berries on CVD risk factors. We examined the hypothesis that freeze-dried strawberries (FDS) improve lipid and lipoprotein profiles and lower biomarkers of inflammation and lipid oxidation in adults with abdominal adiposity and elevated serum lipids. In a randomized dose-response controlled trial, 60 volunteers [5 men and 55 women; aged 49 ± 10 y; BMI: 36 ± 5 kg/m(2) (means ± SDs)] were assigned to consume 1 of the following 4 beverages for 12 wk: 1) low-dose FDS (LD-FDS; 25 g/d); 2) low-dose control (LD-C); 3) high-dose FDS (HD-FDS; 50 g/d); and 4) high-dose control (HD-C). Control beverages were matched for calories and total fiber. Blood draws, anthropometrics, blood pressure, and dietary data were collected at screening (0 wk) and after 12-wk intervention. Dose-response analyses revealed significantly greater decreases in serum total and LDL cholesterol and nuclear magnetic resonance (NMR)-derived small LDL particle concentration in HD-FDS [33 ± 6 mg/dL, 28 ± 7 mg/dL, and 301 ± 78 nmol/L, respectively (means ± SEMs)] vs. LD-FDS (-3 ± 11 mg/dL, -3 ± 9 mg/dL, and -28 ± 124 nmol/L, respectively) over 12 wk (0-12 wk; all P < 0.05). Compared with controls, only the decreases in total and LDL cholesterol in HD-FDS remained significant vs. HD-C (0.7 ± 12 and 1.4 ± 9 mg/dL, respectively) over 12 wk (0-12 wk; all P < 0.05). Both doses of strawberries showed a similar decrease in serum malondialdehyde at 12 wk (LD-FDS: 1.3 ± 0.2 µmol/L; HD-FDS: 1.2 ± 0.1 µmol/L) vs. controls (LD-C: 2.1 ± 0.2 µmol/L; HD-C: 2.3 ± 0.2 µmol/L) (P < 0.05). In general, strawberry intervention did not affect any measures of adiposity, blood pressure, glycemia, and serum concentrations of HDL cholesterol and triglycerides, C-reactive protein, and adhesion molecules. Thus, HD-FDS exerted greater effects in lowering serum total and LDL cholesterol and NMR-derived small LDL particles vs. LD-FDS in the 12-wk study. These findings warrant additional investigation in larger trials. This trial was registered at clinicaltrials.gov as NCT01883401.

Strawberry as a functional food: an evidence-based review.

Emerging research provides substantial evidence to classify strawberries as a functional food with several preventive and therapeutic health benefits. Strawberries, a rich source of phytochemicals (ellagic acid, anthocyanins, quercetin, and catechin) and vitamins (ascorbic acid and folic acid), have been highly ranked among dietary sources of polyphenols and antioxidant capacity. It should however be noted that these bioactive factors can be significantly affected by differences in strawberry cultivars, agricultural practices, storage, and processing methods: freezing versus dry heat has been associated with maximum retention of strawberry bioactives in several studies. Nutritional epidemiology shows inverse association between strawberry consumption and incidence of hypertension or serum C-reactive protein; controlled feeding studies have identified the ability of strawberries to attenuate high-fat diet induced postprandial oxidative stress and inflammation, or postprandial hyperglycemia, or hyperlipidemia in subjects with cardiovascular risk factors. Mechanistic studies have elucidated specific biochemical pathways that might confer these protective effects of strawberries: upregulation of endothelial nitric oxide synthase (eNOS) activity, downregulation of NF-kB activity and subsequent inflammation, or inhibitions of carbohydrate digestive enzymes. These health effects may be attributed to the synergistic effects of nutrients and phytochemicals in strawberries. Further studies are needed to define the optimal dose and duration of strawberry intake in affecting levels of biomarkers or pathways related to chronic diseases.

Seizure control: a secondary benefit of chemotherapeutic temozolomide in brain cancer patients.

The severity of brain tumor associated seizures often mirror the growth of the underlying tumor, and may be intractable to conventional antiepileptic drugs. We present a patient with intractable seizures in the setting of a low grade glioma who responded dramatically to temozolomide despite minimal radiographic change in tumor size. Temozolomide is an effective treatment for seizure control in patients with brain tumors.

Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients.

BACKGROUND: Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion. METHODS: Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments. RESULTS: Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis. CONCLUSIONS: The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.