Life Extension Magazine®

Issue: Aug 2016

Sleep Conference, Colon Cancer Prevention, Homocysteine, and Microdermabrasion

Sleep Conference, Colon Cancer Prevention, Homocysteine, and Microdermabrasion

By Life Extension.

Sleep Conference

Alpha1-Blockers Improve Benign Prostatic Obstruction in Men with Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis of Urodynamic Studies.

CONTEXT: The urodynamic outcomes for alpha1-blockers (ABs) treatment in patients with lower urinary tract symptoms related to benign prostatic enlargement (LUTS/BPE) is a matter of debate. OBJECTIVE: To perform a systematic review and meta-analysis of studies evaluating the ABs urodynamic outcomes in patients with LUTS/BPE. The primary endpoint was variation in bladder outlet obstruction index (BOOI). Secondary endpoints were the maximum urinary flow rate (Qmax) and detrusor pressure at Qmax (PdetQmax). A meta-analysis of placebo-controlled randomized clinical trials (RCTs) was performed to compare ABs with placebo. EVIDENCE ACQUISITION: A systematic review of PubMed/Medline, ISI Web of Knowledge, and Scopus databases was performed in May 2015. Seventeen studies were selected for inclusion. EVIDENCE SYNTHESIS: The overall pooled data showed a mean BOOI change of -14.19 (p<0.0001), a mean PdetQmax change of -11. 39cm H2O (p<0.0001), and a mean Qmax improvement of 2.27ml/s (p<0.0001). Subgroup analysis showed a mean BOOI change of -14.88 (p=0.01) for alfuzosin, -19.41 (p=0.01) for doxazosin, -16.47 (p<0.0001) for naftopidil, -30.45 (p<0.0001) for silodosin, -14.27 (p=0.002) for tamsulosin, and -6.69 (p=0.005) for terazosin. Subanalysis of RCTs containing a placebo arm showed a significant improvement in BOOI in patients undergoing ABs treatment. Meta-regression revealed a significant positive association between the percentage of patients with obstruction at baseline and the improvement in BOOI after treatment with ABs. CONCLUSION: ABs improve BOOI in patients with LUTS/BPE mainly by reducing PdetQmax, and this effect is higher in patients presenting with urodynamic obstruction at baseline. The free Qmax variation underestimates the real effect of ABs on benign prostatic obstruction. PATIENT SUMMARY: Results of this meta-analysis suggest that alpha1-blockers objectively improve urinary voiding function in patients with benign prostatic obstruction.

Eur Urol . 2016 Jan 28.

Sleep-wake regulation and its impact on working memory performance: the role of adenosine.

The sleep-wake cycle is regulated by a fine-tuned interplay between sleep-homeostatic and circadian mechanisms. Compelling evidence suggests that adenosine plays an important role in mediating the increase of homeostatic sleep pressure during time spent awake and its decrease during sleep. Here, we summarize evidence that adenosinergic mechanisms regulate not only the dynamic of sleep pressure, but are also implicated in the interaction of homeostatic and circadian processes. We review how this interaction becomes evident at several levels, including electrophysiological data, neuroimaging studies and behavioral observations. Regarding complex human behavior, we particularly focus on sleep-wake regulatory influences on working memory performance and underlying brain activity, with a specific emphasis on the role of adenosine in this interplay. We conclude that a change in adenosinergic mechanisms, whether exogenous or endogenous, does not only impact on sleep-homeostatic processes, but also interferes with the circadian timing system.

Biology (Basel) . 2016 5(1).

The neurobiology, investigation, and treatment of chronic insomnia.

Chronic insomnia is defined by difficulties in falling asleep, maintaining sleep, and early morning awakening, and is coupled with daytime consequences such as fatigue, attention deficits, and mood instability. These symptoms persist over a period of at least 3 months (Diagnostic and Statistical Manual 5 criteria). Chronic insomnia can be a symptom of many medical, neurological, and mental disorders. As a disorder, it incurs substantial health-care and occupational costs, and poses substantial risks for the development of cardiovascular and mental disorders, including cognitive deficits. Family and twin studies confirm that chronic insomnia can have a genetic component (heritability coefficients between 42% and 57%), whereas the investigation of autonomous and central nervous system parameters has identified hyperarousal as a final common pathway of the pathophysiology, implicating an imbalance of sleep-wake regulation consisting of either overactivity of the arousal systems, hypoactivity of the sleep-inducing systems, or both. Insomnia treatments include benzodiazepines, benzodiazepine-receptor agonists, and cognitive behavioural therapy. Treatments currently under investigation include transcranial magnetic or electrical brain stimulation, and novel methods to deliver psychological interventions.

Lancet Neurol . 2015 May; 14(5): 547-558.

TNFalpha G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults.

Cytokines such as TNFalpha play an integral role in sleep/wake regulation and have recently been hypothesized to be involved in cognitive impairment due to sleep deprivation. We examined the effect of a guanine to adenine substitution at position 308 in the TNFalpha gene (TNFalpha G308A) on psychomotor vigilance performance impairment during total sleep deprivation. A total of 88 healthy women and men (ages 22-40) participated in one of five laboratory total sleep deprivation experiments. Performance on a psychomotor vigilance test (PVT) was measured every 2-3h. The TNFalpha 308A allele, which is less common than the 308G allele, was associated with greater resilience to psychomotor vigilance performance impairment during total sleep deprivation (regardless of time of day), and also provided a small performance benefit at baseline. The effect of genotype on resilience persisted when controlling for between-subjects differences in age, gender, race/ethnicity, and baseline sleep duration. The TNFalpha G308A polymorphism predicted less than 10% of the overall between-subjects variance in performance impairment during sleep deprivation. Nonetheless, the differential effect of the polymorphism at the peak of performance impairment was more than 50% of median performance impairment at that time, which is sizeable compared to the effects of other genotypes reported in the literature. Our findings provided evidence for a role of TNFalpha in the effects of sleep deprivation on psychomotor vigilance performance. Furthermore, the TNFalpha G308A polymorphism may have predictive potential in a biomarker panel for the assessment of resilience to psychomotor vigilance performance impairment due to sleep deprivation.

Brain Behav Immun . 2015 Jul; 47: 66-74.

Sleep, cognition, and normal aging: integrating a half century of multidisciplinary research.

Sleep is implicated in cognitive functioning in young adults. With increasing age, there are substantial changes to sleep quantity and quality, including changes to slow-wave sleep, spindle density, and sleep continuity/fragmentation. A provocative question for the field of cognitive aging is whether such changes in sleep physiology affect cognition (e.g., memory consolidation). We review nearly a half century of research across seven diverse correlational and experimental domains that historically have had little crosstalk. Broadly speaking, sleep and cognitive functions are often related in advancing age, though the prevalence of null effects in healthy older adults (including correlations in the unexpected, negative direction) indicates that age may be an effect modifier of these associations. We interpret the literature as suggesting that maintaining good sleep quality, at least in young adulthood and middle age, promotes better cognitive functioning and serves to protect against age-related cognitive declines.

Perspect Psychol Sci . 2015 Jan; 10(1): 97-137.

Phenotypic vulnerability of energy balance responses to sleep loss in healthy adults.

Short sleep duration is a risk factor for increased hunger and caloric intake, late-night eating, attenuated fat loss when dieting, and for weight gain and obesity. It is unknown whether altered energy-balance responses to sleep loss are stable (phenotypic) over time, and the extent to which individuals differ in vulnerability to such responses. Healthy adults experienced two laboratory exposures to sleep restriction separated by 60-2132 days. Caloric intake, meal timing and weight were objectively measured. Although there were substantial phenotypic differences among participants in weight gain, increased caloric intake, and late-night eating and fat intake, responses within participants showed stability across sleep restriction exposures. Weight change was consistent in both normal-weight and overweight adults. Weight change and increased caloric intake were more stable in men whereas late-night eating was consistent in both genders. This is the first evidence of phenotypic differential vulnerability and trait-like stability of energy balance responses to repeated sleep restriction, underscoring the need for biomarkers and countermeasures to predict and mitigate this vulnerability.

Sci Rep . 2015 5: 14920.

Obstructive sleep apnoea syndrome and its management.

Obstructive sleep apnoea (OSA) is a common disorder characterized by repetitive episodes of nocturnal breathing cessation due to upper airway collapse. OSA causes severe symptoms, such as excessive daytime somnolence, and is associated with a significant cardiovascular morbidity and mortality. Different treatment options are now available for an effective management of this disease. After more than three decades from its first use, continuous positive airway pressure (CPAP) is still recognized as the gold standard treatment. Nasal CPAP (nCPAP) is highly effective in controlling symptoms, improving quality of life and reducing the clinical sequelae of sleep apnoea. Other positive airway pressure modalities are available for patients intolerant to CPAP or requiring high levels of positive pressure. Mandibular advancement devices, particularly if custom made, are effective in mild to moderate OSA and provide a viable alternative for patients intolerant to CPAP therapy. The role of surgery remains controversial. Uvulopalatopharyngoplasty is a well established procedure and can be considered when treatment with CPAP has failed, whereas maxillar-mandibular surgery can be suggested to patients with a craniofacial malformation. A number of minimally invasive procedures to treat snoring are currently under evaluation. Weight loss improves symptoms and morbidity in all patients with obesity and bariatric surgery is an option in severe obesity. A multidisciplinary approach is necessary for an accurate management of the disease.

Ther Adv Chronic Dis . 2015 Sep; 6(5): 273-285.

Feedback Blunting: Total Sleep Deprivation Impairs Decision Making that Requires Updating Based on Feedback.

STUDY OBJECTIVES: To better understand the sometimes catastrophic effects of sleep loss on naturalistic decision making, we investigated effects of sleep deprivation on decision making in a reversal learning paradigm requiring acquisition and updating of information based on outcome feedback. DESIGN: Subjects were randomized to a sleep deprivation or control condition, with performance testing at baseline, after 2 nights of total sleep deprivation (or rested control), and following 2 nights of recovery sleep. Subjects performed a decision task involving initial learning of go and no go response sets followed by unannounced reversal of contingencies, requiring use of outcome feedback for decisions. A working memory scanning task and psychomotor vigilance test were also administered. SETTING: Six consecutive days and nights in a controlled laboratory environment with continuous behavioral monitoring. SUBJECTS: Twenty-six subjects (22-40 y of age; 10 women). INTERVENTIONS: Thirteen subjects were randomized to a 62-h total sleep deprivation condition; the others were controls. MEASUREMENTS AND RESULTS: Unlike controls, sleep deprived subjects had difficulty with initial learning of go and no go stimuli sets and had profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Working memory scanning performance was not significantly affected by sleep deprivation. And although sleep deprived subjects showed expected attentional lapses, these could not account for impairments in reversal learning decision making. CONCLUSIONS: Sleep deprivation is particularly problematic for decision making involving uncertainty and unexpected change. Blunted reactions to feedback while sleep deprived underlie failures to adapt to uncertainty and changing contingencies. Thus, an error may register, but with diminished effect because of reduced affective valence of the feedback or because the feedback is not cognitively bound with the choice. This has important implications for understanding and managing sleep loss-induced cognitive impairment in emergency response, disaster management, military operations, and other dynamic real-world settings with uncertain outcomes and imperfect information

Sleep . 2015 May; 38(5): 745-754.

Colon Cancer Prevention

Endoscopic Improvement of the Adenoma Detection Rate during Colonoscopy - Where Do We Stand in 2015?

BACKGROUND: The presence of colorectal adenomas is considered a major risk factor for colorectal cancer development. The implementation of screening colonoscopy programs in the Western world has led to a substantial reduction of colorectal cancer death. Many efforts have been made to reduce the adenoma miss rates by the application of new endoscopic devices and techniques for better adenoma visualization. SUMMARY: This special review gives the readership an overview of current endoscopic innovations that can aid in the increase of the adenoma detection rate (ADR) during colonoscopy. These innovations include the use of devices like EndoCuff(R) and EndoRings(R) as well as new technical equipment like third-eye endoscope(R) and full-spectrum endoscopy (FUSE(R)). Key Message: Technical improvements and newly developed accessories are able to improve the ADR. However, additional costs and a willingness to invest into potentially expensive equipment might be necessary. Investigator-dependent skills remain the backbone in the ADR detection.

Digestion . 2016 93(3): 202-213.

Effects of physical activity on risk of colorectal cancer: a case-control study.

BACKGROUND: The prevalence of colorectal cancer (CRC) is rapidly increasing in Iran. It holds the most prevalent cancer after skin, breast, and gastric cancers among the Iranian population. The current study was designed to investigate the effects of leisure time, occupational and household physical activity as well as exercise on the risk of CRC in the Iranian population. METHODS: In this population-based case-control study, 100 individuals with a recent diagnosis of CRC who were eligible for the study were recruited between 2006 and 2008. The control groups were selected from patients' companions (excluding first- and second-degree relatives) without past history of cancer or any physical disability. Physical activity of the participants was evaluated using a Kriska retrospective physical activity questionnaire. The relation between CRC and physical activity was assessed via logistic regression model and calculating the odds ratio (OR) as well as a confidence interval (CI) of 95%. RESULTS: According to the findings, the adjusted OR of occupational (OR = 0.98, 95%, CI: 0.95-1.02) and house holding physical activities (OR = 1.03, 95% CI: 0.99-1.08) were not significantly different between the case and control groups for women (P > 0.05). The risk of CRC shows a significant reduction in individuals with moderate leisure physical activities compared to those with minimal activities (OR = 0.82, CI 95%: 0.73-0.98). CONCLUSIONS: The study suggests that the risk of CRC will decrease in individuals with higher leisure physical activities (especially with an increase in hours of brisk walking during the day).

Int J Prev Med . 2016 7: 32.

Metformin is associated with slightly reduced risk of colorectal cancer and moderate survival benefits in diabetes mellitus: a meta-analysis.

To systematically assess the effect of metformin on colorectal cancer (CRC) risk and mortality in type 2 diabetes mellitus (T2DM) patients.We conducted a systematic search of PubMed, Web of Science, and the Cochrane Library databases for relevant articles before August 2015. Two investigators identified and extracted data independently. We adopted adjusted estimates to calculate summary estimates with 95% confidence interval (CI) using either a fixed-effects or a random-effects model. Subgroup and sensitivity analyses were conducted to evaluate the robustness of the pooled results. The risk of publication bias was assessed by examining funnel plot asymmetry as well as Begg test and Egger test.Fifteen studies on CRC incidence and 6 studies on CRC survival were finally included in our meta-analysis. The pooled odds ratio (OR) of observational studies illustrated that a slight 10% reduction of CRC incidence was associated with metformin use (OR = 0.90, 95% CI: 0.85-0.96). Furthermore, the pooled hazard ratio (HR) revealed an improved survival outcome for metformin users in CRC patients compared to nonusers (HR = 0.68, 95% CI: 0.58-081). There was no publication bias across studies.Our meta-analysis demonstrated that metformin therapy could slightly reduce CRC incidence and moderately improve the survival outcomes in patients with T2DM. More prospective studies are warranted to certify this protective association.

Medicine (Baltimore) . 2016 Feb; 95(7): e2749.

Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial.

BACKGROUND: The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. METHODS: This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. FINDINGS: Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38.0%; 95% CI 26.7-49.3] of 71 patients, placebo group 35 [56.5%; 95% CI 44.1-68.8] of 62; p=0.034, risk ratio [RR] 0.67 [95% CI 0.47-0.97]; adenomas: metformin group 22 [30.6%; 95% CI 19.9-41.2] of 71 patients, placebo group 32 [51.6%; 95% CI 39.2-64.1] of 62; p=0.016, RR 0.60 [95% CI 0.39-0.92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0.041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0.037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. INTERPRETATION: The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. FUNDING: Ministry of Health, Labour and Welfare, Japan.

Lancet Oncol . 2016 Mar 2.

Curcumin induces apoptosis of colorectal cancer stem cells by coupling with CD44 marker.

This study investigated the effect of curcumin on colorectal cancer stem cells (CCSCs) and its possible mechanism. Comparison of the metabolic profiles of human adenomatous polyp (N = 61) and colorectal cancer (CRC) (N = 57) tissue found statistically significant differences (p < 0.05) in their composition of adenosine monophosphate (AMP), adenine, 5'-methythioadenosine, 3-hydroxybutyric acid, prostaglandin E2, threonine, and glutamine. Our cell culture model study found that curcumin treatment (50 muM for 48 h) did indeed increase apoptosis of CRC cells as well as of CCSCs, but at a significant level only in CD44(+) cells. Further metabolic profile studies of the CRC, CD44(+), and CD44(-) cells indicated that curcumin treatment increased glyceraldehyde and hydroxypropionic acid in CD44(-) cells but decreased glutamine content in both curcumin-treated CRC and CD44(+) cells. Based on our comparison of the metabolic profiles of human tissues and cancer cells, we suggest that curcumin might couple with CD44 and that curcumin-CD44(+) coupling at the cell membrane might have some blocking effect on the transport of glutamine into the cells, thus decreasing the glutamine content in the CD44(+) cells and inducing apoptosis.

J Agric Food Chem . 2016 Mar 23; 64(11): 2247-2253.

Chromoendoscopy with a standard-resolution colonoscope for evaluation of rectal aberrant crypt foci.

Colorectal cancer (CRC) is the second most common cause of death worldwide. According to the theory by Vogelstein, colorectal carcinogenesis involves a series of successive changes in the normal colonic mucosa, starting with excessive proliferation and focal disorders of intestinal crypts, followed by adenoma and its subsequent malignant transformation. The first identifiable changes in CRC carcinogenesis are aberrant crypt foci (ACF). ACF are invisible during routine colonoscopy yet are well identifiable in chromoendoscopy using methylene blue or indigo carmine. High-resolution colonoscopes are used for assessment of ACF. The aim of the present study was to evaluate the usefulness of standard-resolution colonoscopy for identification of rectal ACF. The following parameters were evaluated: duration of chromoendoscopy of a given rectal segment, type of ACF, sensitivity and specificity of endoscopy combined with histopathological evaluation. The mean duration of colonoscopy and chromoendoscopy was 26.8 min. In the study population, typical ACF were found in 73 patients (p = 0.489), hyperplastic ACF in 49 (p = 0.328), and dysplastic ACF in 16 patients (p = 0.107). Mixed ACF were observed in 11 individuals (p = 0.073). The sensitivity of the method was found to be 0.96 whereas its specificity 0.99. Identification of rectal ACF using standard-resolution colonoscopy combined with rectal mucosa staining with 0.25% methylene blue is characterised by high sensitivity and specificity.

PLoS One . 2016 11(2): e0148286.

Protective links between vitamin D, inflammatory bowel disease and colon cancer.

Vitamin D deficiency has been associated with a wide range of diseases and multiple forms of cancer including breast, colon, and prostate cancers. Relatively recent work has demonstrated vitamin D to be critical in immune function and therefore important in inflammatory diseases such as inflammatory bowel disease (IBD). Because vitamin D deficiency or insufficiency is increasingly prevalent around the world, with an estimated 30%-50% of children and adults at risk for vitamin D deficiency worldwide, it could have a significant impact on IBD. Epidemiologic studies suggest that low serum vitamin D levels are a risk factor for IBD and colon cancer, and vitamin D supplementation is associated with decreased colitis disease activity and/or alleviated symptoms. Patients diagnosed with IBD have a higher incidence of colorectal cancer than the general population, which supports the notion that inflammation plays a key role in cancer development and underscores the importance of understanding how vitamin D influences inflammation and its cancer-promoting effects. In addition to human epidemiological data, studies utilizing mouse models of colitis have shown that vitamin D is beneficial in preventing or ameliorating inflammation and clinical disease. The precise role of vitamin D on colitis is unknown; however, vitamin D regulates immune cell trafficking and differentiation, gut barrier function and antimicrobial peptide synthesis, all of which may be protective from IBD and colon cancer. Here we focus on effects of vitamin D on inflammation and inflammation-associated colon cancer and discuss the potential use of vitamin D for protection and treatment of IBD and colon cancer.

World J Gastroenterol . 2016 Jan 21; 22(3): 933-948.

Inhibition of NF-kappaB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer.

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth and resistance. Thymidylate synthase (TS) is a therapeutic target for 5FU. Curcumin is a potent inhibitor of NF-kappaB. EF31 and UBS109 are potent synthetic analogues of curcumin. We tested the hypothesis that inhibition of NF-kappaB translocation by curcumin and its analogs EF31 and UBS109 can inhibit cell cycle progression and downregulate TS levels in colorectal cancer (CRC) cell lines. Two CRC cell lines (HCT116 and HT-29) were either untreated (control) or treated with IC50 concentrations of curcumin, EF31 UBS109 led to G0/G1 cell cycle arrest. Treatment with curcumin, EF31 or UBS109 inhibited NF-kappaB, downregulated survival pathways and inhibited cell cycle progression. Arrest in the G0/G1 phase was associated with downregulation of the transcription factor E2F-1 and its target gene TS. NF-kappaB over-expression induced E2F-1 and TS protein and mRNA levels in both cell lines. EF31 and UBS109 treatment significantly decreased tumor growth in compared to untreated tumors. EF31 and UBS109 are promising agents for the prevention and treatment of CRC.

Cancer Lett . 2016 Apr 10; 373(2): 227-233.

Selenite-induced autophagy antagonizes apoptosis in colorectal cancer cells in vitro and in vivo.

In the present study, we aimed to investigate the relationship between autophagy and apoptosis in selenitetreated colorectal cancer (CRC) cells. The effects of selenite on HCT116 and SW480 cell apoptosis were investigated with an Annexin V/propidium iodide (PI) double staining kit by flow cytometry. The punctate of LC3 protein following treatment with selenite was observed by a laser scanning confocal microscope and by transmission electron microscopy. Using western blot assays, we detected the apoptotic and autophagic markers in both CRC cells and mouse xenograft tumor models. We found that sodium selenite induced autophagy in the two CRC cell lines. Consistent with the in vitro results, we observed that the expression of autophagy marker LC3 was increased. Finally, we discovered that modulation of reactive oxygen species by MnTMPyP inhibited autophagy, while H2O2 activated autophagy. These results help to elucidate the anticancer effect of selenium, providing further evidence to exploit novel anticancer drugs targeting selenium.

Oncol Rep . 2016 Mar; 35(3): 1255-1264.


Homocysteine and serotonin: association with postpartum depression.

Postpartum depression (PPD) is a disorder of multifactorial origin with significant consequences on both maternal and child health. One of the biological factors implicated is perturbed methionine-homocysteine metabolism. Since this metabolic pathway plays a significant role in myelination of nerve fibers, the growth and development of the child would also be adversely affected. We carried out this study in 103 women (58 with PPD and 45 without PPD) who delivered their child in our institute from December 2010 to November 2011. The study group was evaluated for PPD using Edinburgh postnatal depression scale with a cut-off score of 10. Assessment of fetal well being was done by APGAR score assessed immediately after birth. Serum folic acid, vitamin B12, homocysteine and serotonin was done by ELISA. We found significantly elevated levels of homocysteine in women with PPD as compared to those without PPD, both at 24-48h as well as six weeks after delivery, although no associations were found with folate and vitamin B12 levels. Also, there was a significant negative correlation between serum homocysteine and serotonin levels in the postpartum depression group with a significant negative correlation between homocysteine and serotonin. Our study showed a significantly lower APGAR score in the infants born to mothers with PPD. Our study also shows that homocysteinemia is associated with PPD whether at the first week or sixth week, while low serum serotonin may play a role in depression during the first week, but may not have a role in depression status at the sixth week. Also, PPD in the mother is related to a low APGAR score in infants born to these mothers emphasizing the significance of both mental as well as nutritional status of the mother.

Asian J Psychiatr . 2013 Dec; 6(6): 473-477.

Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies.

Background Late-life depression may increase the risk of incident dementia, in particular of Alzheimer’s disease and vascular dementia. Aims To conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia, Alzheimer’s disease and vascular dementia in individuals with late-life depression in population-based prospective studies. Method A total of 23 studies were included in the meta-analysis. We used the generic inverse variance method with a random-effects model to calculate the pooled risk of dementia, Alzheimer’s disease and vascular dementia in older adults with late-life depression. Results Late-life depression was associated with a significant risk of all-cause dementia (1.85, 95% CI 1.67-2.04, P&lt;0.001), Alzheimer’s disease (1.65, 95% CI 1.42-1.92, P&lt;0.001) and vascular dementia (2.52, 95% CI 1.77-3.59, P&lt;0.001). Subgroup analysis, based on five studies, showed that the risk of vascular dementia was significantly higher than for Alzheimer’s disease (P = 0.03). Conclusions Late-life depression is associated with an increased risk for all-cause dementia, vascular dementia and Alzheimer’s disease. The present results suggest that it will be valuable to design clinical trials to investigate the effect of late-life depression prevention on risk of dementia, in particular vascular dementia and Alzheimer’s disease.

The British Journal of Psychiatry . 2013 202(5): 329-335.

The role of L-methylfolate in depressive disorders.

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for approximately 30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

CNS Spectr . 2009 Jan; 14(1 Suppl 2): 2-7.

L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode.

OBJECTIVE: Evaluate the efficacy of L-methylfolate in combination with SSRI or SNRI compared to SSRI or SNRI monotherapy in a major depressive episode. DESIGN: A retrospective analysis of L-methylfolate plus SSRI/SNRI at treatment initiation (n=95) and SSRI/SNRI monotherapy (n=147) from patient charts. SETTING: Outpatient, private psychiatric clinic/practice. PARTICIPANTS: Adults 18 to 70 with major depressive episode (single or recurrent). MEASUREMENTS: Clinical Global Impressions-Severity (CGI-S) and safety/tolerability measures. RESULTS: Major improvement (CGI-S reduced by >/=2 points) was experienced by 18.5 percent of L-methylfolate plus SSRI/SNRI patients (CGI-S=4-5) compared to 7.04 percent of SSRI/SNRI monotherapy (p=0.01) patients at 60 days. Forty percent of L-methylfolate plus SSRI/SNRI patients with greater functional impairment (CGI-S=5) experienced major improvement compared to 16.3 percent of SSRI/SNRI monotherapy patients (p=0.02). Median times to major improvement were 177 days for L-methylfolate plus SSRI/SNRI patients and 231 days for SSRI/SNRI monotherapy patients (p=0.03). Median time to major improvement for L-methylfolate plus SSRI/SNRI patients with greater functional impairment (CGI-S=5) was 85 days and 150 days for SSRI/SNRI monotherapy patients (p=0.018). There were no significant differences between groups in adverse events. Discontinuation due to adverse events was 17.9 percent in L-methylfolate plus SSRI/SNRI patients compared to 34 percent in the SSRI/SNRI monotherapy patients over duration of the study (p=0.0078). CONCLUSION: L-methylfolate plus antidepressant at treatment onset was more effective in improving depressive symptoms and function measured by CGI-S scores within 60 days than antidepressant monotherapy, led to major symptomatic improvement more rapidly than SSRI/SNRI monotherapy, and was better tolerated.

Innov Clin Neurosci . 2011 Jan; 8(1): 19-28.

Comprehensive evaluation of postpartum depression and correlations between postpartum depression and serum levels of homocysteine in Chinese women.

OBJECTIVE: To investigate whether the level of homocysteine in patients with postpartum depression is associated with depression index. METHODS: A total of 43 women with postpartum depression or with potential postpartum depression, who visited the psychological clinic of Maternal and Child Health Hospital of Hunan Province from June, 2012 to April, 2014, were enrolled in this study. They were evaluated by the Edinburgh Postnatal Depression Scale and Hamilton Depression Scale. Chinese Classification of Mental Disorder (the third edition) was used for their diagnosis. The depressive index was calculated by Edinburgh Postnatal Depression Scale, Hamilton Depression Scale, and clinical symptom scores, which was used to assess the level of depressive symptoms. The level of homocysteine in serum was detected by chemoluminescent method. Meanwhile, another 31 women, who visited the hospital without postpartum depression, were used as controls to compare with the 43 patients. RESULTS: The homocysteine level in the women with postpartum depression was significantly higher than that in the control group [(10.09 +/- 3.59) mumol/L vs (8.57 +/- 1.59) mumol/L, t=12.392, P=0.001]. The depression index was positively correlated with the level of homocysteine (r=0.231, P<0.05). CONCLUSION: The level of serum homocysteine is associated with postpartum depression, suggesting that the level of serum homocysteine might be a risk biomarker for postpartum depression.

Zhong Nan Da Xue Xue Bao Yi Xue Ban . 2015 Mar; 40(3): 311-316.

Suffering in silence: a qualitative meta-data-analysis of postpartum depression.

In this article, we apply a relational lens to a grounded theory meta-data-analysis of qualitative studies on postpartum depression (PPD) conducted between 1999 and 2005. Women in all studies report feeling that they have failed to live up to cultural standards for a "good mother." Central to this experience is a sense that these negative feelings could not be spoken. The analysis shows how constructions of motherhood and the reactions of others combine with feelings of incompetence to precipitate isolation from others. Women survive depression through support that validates their experience and promotes eventual reconnection with others. Conclusions emphasize the need for persons trained to facilitate relational connection to develop interventions that address the interpersonal contexts of PPD.

J Marital Fam Ther . 2009 Apr; 35(2): 145-158.

Folates and S-adenosylmethionine for major depressive disorder.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased signi fi cantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, ef fi cacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium.

Can J Psychiatry . 2012 Jul; 57(7): 406-413.

[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase.

BACKGROUND AND PURPOSE: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C-->T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C-->T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives. EXPERIMENTAL APPROACH: Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (C(max)) and time-to-reach-maximum (t(max)) were calculated. KEY RESULTS: AUC and C(max) were significantly higher, and t(max) significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for t(max) after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF. CONCLUSIONS AND IMPLICATIONS: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C-->T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification.

Br J Pharmacol . 2009 Dec; 158(8): 2014-2021.


Characteristics of the Aging Skin.

SIGNIFICANCE: Although most researches into the changes in skin with age focus on the unwelcome aesthetic aspects of the aging skin, skin deterioration with age is more than a merely cosmetic problem. Although mortality from skin disease is primarily restricted to melanoma, dermatological disorders are ubiquitous in older people with a significant impact on quality of life. The structural and functional deterioration of the skin that occurs with age has numerous clinical presentations, ranging from benign but potentially excruciating disorders like pruritus to the more threatening carcinomas and melanomas. RECENT ADVANCES: The degenerative changes that occur in the aging skin are increasingly understood at both the molecular and cellular level, facilitating a deeper understanding of the structural and functional deterioration that these changes produce. CRITICAL ISSUES: A loss of both function and structural stability in skin proceeds unavoidably as individuals age, which is the result of both intrinsic and extrinsic processes, which contribute simultaneously to a progressive loss of skin integrity. Intrinsic aging proceeds at a genetically determined pace, primarily caused by the buildup of damaging products of cellular metabolism as well as an increasing biological aging of the cells. Estrogen levels strongly influence skin integrity in women as well; falling levels in midlife, therefore, produce premature aging as compared with similarly aged men. Extrinsic insults from the environment add to the dermatological signs of aging. FUTURE DIRECTIONS: A deeper understanding of the physiological basis of skin aging will facilitate progress in the treatment of the unwelcome sequelae of aging skin, both cosmetic and pathogenic.

Adv Wound Care (New Rochelle) . 2013 Feb; 2(1): 5-10.

Topical antioxidant application enhances the effects of facial microdermabrasion.

BACKGROUND: Microderma-brasion has been accepted as a reliable, non-invasive method for facial rejuvenation. Recently, there has been interest in combining this technique with other modalities to increase its efficacy. The purpose of this study was to determine whether the addition of an antioxidant-based serum enhanced the dermatologic changes seen following microdermabrasion. METHODS: Ten female volunteers, aged 38-52 years, underwent a series of six diamond tip crystal-free microdermabrasion facial treatments spaced 7-10 days apart. An antioxidant serum rich in polyphenols was pneumatically applied to half the face immediately after each microdermabrasion treatment. Skin biopsies and skin polyphenolic antioxidant levels, determined by Raman spectroscopy, were obtained prior to and after the study period. Investigator ratings for efficacy were analyzed after the study period and compared to baseline. RESULTS: Compared with the skin treated with microdermabrasion only, the skin treated with microdermabrasion plus antioxidant demonstrated significantly increased epidermal and papillary dermal thickness, and increased fibroblast density (p < 0.01). There was increased hyalinization of the papillary dermis with newly deposited collagen fibers. Skin polyphenolic antioxidant levels increased 32% in the skin treated with the polyphenolic antioxidant serum after microdermabrasion (p < 0.01). Clinical efficacy variables were significantly more improved in the antioxidant group when compared to baseline (p < 0.01). These changes were supported clinically via digital photography. CONCLUSION: The addition of a polyphenolic antioxidant serum to a facial microdermabrasion regimen enhanced the clinical and histological changes seen following microdermabrasion alone. This combination should strengthen the use of microdermabrasion as a non-invasive facial rejuvenation tool and support the role of topical antioxidants as anti-aging factors.

J Dermatolog Treat . 2009 20(2): 82-87.

Menthol pain relief through cumulative inactivation of voltage-gated sodium channels.

Menthol is a natural compound of plant origin known to produce cool sensation via the activation of the TRPM8 channel. It is also frequently part of topical analgesic drugs available in a pharmacy, although its mechanism of action is still unknown. Compelling evidence indicates that voltage-gated Na(+) channels are critical for experiencing pain sensation. We tested the hypothesis that menthol may block voltage-gated Na(+) channels in dorsal root ganglion (DRG) neurons. By use of a patch clamp, we evaluated the effects of menthol application on tetrodotoxin (TTX)-resistant Nav1.8 and Nav1.9 channel subtypes in DRG neurons, and on TTX-sensitive Na(+) channels in immortalized DRG neuron-derived F11 cells. The results indicate that menthol inhibits Na(+) channels in a concentration-, voltage-, and frequency-dependent manner. Menthol promoted fast and slow inactivation states, causing use-dependent depression of Na(+) channel activity. In current clamp recordings, menthol inhibited firing at high-frequency stimulation with minimal effects on normal neuronal activity. We found that low concentrations of menthol cause analgesia in mice, relieving pain produced by a Na(+) channel-targeting toxin. We conclude that menthol is a state-selective blocker of Nav1.8, Nav1.9, and TTX-sensitive Na(+) channels, indicating a role for Na(+) channel blockade in the efficacy of menthol as topical analgesic compound.

Pain . 2012 Feb; 153(2): 473-484.

Terpene compounds in nature: a review of their potential antioxidant activity.

Reactive Oxygen Species are involved in the pathological development of many important human diseases such as neurodegenerative diseases, cardiovascular processes, diabetes and many others. The most promising strategy to prevent from the oxidative damage caused by these reactive species is the use of antioxidant molecules. These compounds can act as direct antioxidants through free radical scavenging mechanisms and/or as indirect antioxidants by enhancing the antioxidant status (enzymatic and non-enzymatic). Terpenes, one of the most extensive and varied structural compounds occurring in nature, display a wide range of biological and pharmacological activities. Here we highlight their antioxidant properties. Due to their antioxidant behaviour terpenes have been shown to provide relevant protection under oxidative stress conditions in different diseases including liver, renal, neurodegenerative and cardiovascular diseases, cancer, diabetes as well as in ageing processes. Evidence for this comes from the increasing number of publications on this issue in recent years. This review provides a complete overview of the natural terpenes with potential antioxidant properties, focusing on their source, structures, antioxidant mechanisms through which they exert their pharmacological and possible therapeutic activities.

Curr Med Chem . 2012 19(31): 5319-5341.

Microdermabrasion: an evidence-based review.

Microdermabrasion is a popular technique used in the treatment of several skin problems, including acne, acne scarring, striae distensae, and photoaging. This article will review the relevant literature and use an evidence-based approach to evaluate the clinical efficacy of microdermabrasion in skin care. In summary, microdermabrasion appears to be a procedure that can produce changes in dermal matrix constituents and result in improvement in skin contour irregularities. It may also be beneficial in improving transepidermal delivery of certain medications. Its role in the treatment of dyschromias and acne vulgaris is limited.

Plast Reconstr Surg . 2010 Jan; 125(1): 372-377.

Microdermabrasion: molecular mechanisms unraveled, part 1.

Microdermabrasion (MDA) remains a common in-office procedure for many dermatologic practices.The procedure offers minimal downtime with a low incidence of side effects, making it a relatively desirable option for skin rejuvenation. Investigators have identified many of the molecular mechanisms behind this technology in an attempt to optimize clinical results. In particular, activation of the wound healing response plays a key role in the remodeling of post-MDA treated skin, although this response varies based on the type of MDA employed.While many studies discuss the clinical applications of MDA and their relation to histologic changes found after treatment, few address the basic science behind the technology.Our review covers progress made in the last 10 years of research, with an emphasis on the molecular mechanisms.

J Drugs Dermatol . 2012 Sep; 11(9): e2-9.

Microdermabrasion: molecular mechanisms unraveled, part 2.

Microdermabrasion (MDA) remains a common in-office procedure for many dermatologic practices. The procedure offers minimal downtime with a low incidence of side effects, making it a relatively desirable option for skin rejuvenation. Investigators have identified many of the molecular mechanisms behind this technology in an attempt to optimize clinical results. In particular, activation of the wound healing response plays a key role in the remodeling of post-MDA treated skin, although this response varies based on the type of MDA employed. In addition, advances in MDA technology offer new and promising ways to enhance transcutaneous penetration of active ingredients to improve clinical outcomes. Our review addresses innovative applications of MDA in the last 10 years of research.

J Drugs Dermatol . 2012 Sep; 11(9): e10-17.

Skin resurfacing procedures: new and emerging options.

The demand for skin resurfacing and rejuvenating procedures has progressively increased in the last decade and has sparked several advances within the skin resurfacing field that promote faster healing while minimizing downtime and side effects for patients. Several technological and procedural skin resurfacing developments are being integrated into clinical practices today allowing clinicians to treat a broader range of patients' skin types and pathologies than in years past, with noteworthy outcomes. This article will discuss some emerging and developing resurfacing therapies and treatments that are present today and soon to be available.

Clin Cosmet Investig Dermatol . 2014 7: 231-241.

Jojoba in dermatology: a succinct review.

Phytomedicine has been successfully used in dermatology horizon for thousands of years. Jojoba (Simmondsia chinensis) is a long-lived, drought resistant, perennial plant with interesting economic value as it is processed for liquid wax production. The jojoba plant produces esters of long-chain alcohols and fatty acids (waxes) as a seed lipid energy reserve. The liquid wax is an important substrate for a variety of industrial applications and is used in skin treatment preparations. The oil from the jojoba plant is the main biological source of wax esters and has a multitude of potential applications. The review of literatures suggest that jojoba has anti-inflammatory effect and it can be used on a variety of skin conditions including skin infections, skin aging, as well as wound healing. Moreover, jojoba has been shown to play a role in cosmetics formulas such as sunscreens and moisturizers and also enhances the absorption of topical drugs. The intention of the review is to summarize the data regarding the uses of jojoba in dermatology for readers and researchers.

G Ital Dermatol Venereol . 2013 Dec; 148(6): 687-691.