Sleep, Sirtuin 1 and Alzheimer’s disease: A review

Sleep plays a major role in brain health, and cognition. Disrupted sleep is a well-described symptom of Alzheimer’s disease (AD). However, accumulating evidence suggests suboptimal sleep also increases AD risk. The deacetylase Sirtuin 1 (Sirt 1), encoded by the SIRT1 gene, impacts sleep via its relationship to wake-sleep neurotransmitters and somnogens. Evidence from animal and human studies supports a significant and complex relationship between sleep, Sirt 1/ SIRT1 and AD. Numerous hypotheses attempt to explain the critical impact of Sirt 1/ SIRT1 on wake- and sleep- promoting neurons, their related mechanisms and neurotransmitters. However, there is a paucity of studies assessing the interaction between sleep and Sirt 1/ SIRT1, as a principal component of sleep regulation, on AD pathology. In this review, we explore the potential association between Sirt 1/ SIRT1, sleep, and AD aetiology. Given sleep is a likely modifiable risk factor for AD, and recent studies suggest Sirt 1/ SIRT1 activation can be modulated by lifestyle or dietary approaches, further research in this area is required to explore its potential as a target for AD prevention and treatment

A potential role for sirtuin-1 in Alzheimer\u27s disease: Reviewing the biological and environmental evidence

Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer\u27s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid- and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia

A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years

Background: Esophageal-cancer is the seventh most common-cause of cancer-related-deaths in men. Cytochrome-P450-family-1-subfamily-B-polypeptide-1 (CYP1B1) plays a role in the metabolism of xenobiotics, and is associated with several cancers. Here we investigated the association between a genetic-variant, CYP1B1-rs1056836, with the clinical-characteristics of patients with esophagus-squamous-cell-carcinoma (ESCC). Method: 117-patients with ESCC and 208 healthy-subjects were recruited. DNA was extracted and genotyped. Kaplan-Meier curves were utilized to assess overall and progression-free survival. The relationship between clinicopathological-data, disease-prognosis, and survival, were evaluated with the genotypes. Results: the genotypic frequency for GG, GC, and CC were 58.6%, 29.8%, 11.5% respectively in the healthy subjects and 51.8%, 36.14% and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Conclusion: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger-populations in different-ethnic groups, taking into account potentially important environmental-factors

A variant in CYP2R1 predicts circulating vitamin D levels after supplementation with high-dose of vitamin D in healthy adolescent girls

Aim The determinants of serum vitamin D seems to be the environmental factors (dietary and supplementary intake and exposure to ultraviolet light) and genetic factors. We aimed to study the relationship between a vitamin D‐associated genetic polymorphism and serum 25(OH)D concentrations in healthy adolescent girls in Iran, and its effects on a high‐dose supplement of vitamin D. Material and method A total of 616 healthy adolescent girls with mean age 15 received 50,000 IU of vitamin D3 weekly over 9 weeks. Serum vitamin D levels and other metabolic factors were measured at baseline and after the intervention. The genotyping of the CYP2R1 variant (rs10741657) was performed by TaqMan genotyping assays. Results Regardless of the genetic background, at baseline, 87% of adolescent girls were vitamin D deficient (serum 25(OH)D level < 50 nmol/l). High‐dose supplementation with VitD reduced the proportion of girls who were deficient substantially to about 24%. The genetic analysis revealed that although at baseline there was not a gene‐vitamin D association ( p trend = 0.1), the response to supplementation appeared to be modulated by this variant ( p trend < 0.001). However, other anthropometric and biochemical measures were not affected by this intervention, over this short period. Serum 25(OH)D was increased in all participants although the carriers of the minor A allele seemed to be better responders so that the percentages of the change serum vitamin D in the holder of AA and AG genotypes were 539.4 ± 443.1 and 443.7 ± 384.6, respectively, compared with those with common GG genotype (363.3 ± 354.0). Our regression analysis revealed that the probability of an increase in serum 25(OH)D in a participant with AA genotype was 2.5‐fold greater than those with a GG genotype (OR = 2.5 (1.4–4.4); p value = 0.002). Conclusion Based on our findings, it appears that the rs10741657 variant of the CYP2R1 gene modulates the response to high‐dose of vitamin D supplementation

Associations of vitamin D binding protein variants with the vitamin D-induced increase in serum 25-hydroxyvitamin D

Background: Vitamin D deficiency is a global problem that may be improved by vitamin D supplementation; however, the individual's response to the intervention varies. We aimed to investigate possible genetic factors that may modify the impact of environmental exposure on vitamin D status. The candidate gene variant we investigated was the Gc gene-rs4588 polymorphism at the vitamin D receptor (DBP) locus. Methods: A total of 619 healthy adolescent Iranian girls received 50000 IU of vitamin D3 weekly for 9 weeks. Serum 25(OH) D concentrations, metabolic profiles and dietary intake were measured at baseline and after 9 weeks of supplementation. The genotypes of the DBP variant (rs4588) were analyzed using the TaqMan genotyping assay. Results: Our results revealed that the rs4588 polymorphism might be associated with serum 25-hydroxy vitamin D both at baseline (p value=0.03) and after intervention (p value=0.008). It seemed that the outcome of the intervention was gene-related so that the subjects with common AA genotype were a better responder to vitamin D supplementation (Changes (%) 469.5(427.1) in AA carriers vs. 335.8(530) in GG holders), and carriers of the less common GG genotype experienced a rise in blood glucose after 9 weeks (Changes (%) 0 (1.5)). Our findings also showed that the statistical interaction between this variant and supplementation was statistically significant (intervention effect p-value<0.001 and p-value SNP effect=0.03). The regression model also revealed that after adjusted for potential confounders, likelihood of affecting serum 25(OH)D in individuals who were homozygous for the uncommon allele G was less than those homozygous for the more common AA genotype (OR=4.407 (1.82-8.89); p=0.001). Conclusion: Serum vitamin 25(OH) D following vitamin 25(OH) D3 supplementation appears to be modified by genetic background. The Gc genetic variant, rs4588 encoding the vitamin D receptor seems to influence the response to vitamin D supplementation. Key words: Total 25(OH) D, Supplementation, Gc gene, rs4588

The interaction between a HSP-70 gene variant with dietary calories in determining serum markers of inflammation and cardiovascular risk

Background: The high prevalence of cardiovascular disease (CVD) globally is attributable to an interaction between environmental and genetic factors. Gene × diet interaction studies aim to explore how a modifiable factor interacts with genetic predispositions. Here we have explored the interaction of a heat shock protein (HSP70) gene polymorphism (+1267A>G) with dietary intake and their possible association with serum C-reactive protein (CRP), an inflammatory marker, that is a major component of CVD risk. Methods: HSP70 genotype was determined using a TaqMan real time PCR based method. Genetic variation of the HSP70 gene +1267A>G locus. Dietary intake was assessed using a dietary questionnaire. Serum high sensitivity (Hs) CRP and other cardiovascular risk factors were assessed by routine methods. This included coronary angioplasty to determine the presence of coronary artery stenosis. Results: There were significant differences between serum lipid profile and Hs-CRP across the genotypes for Hsp70. The carriers of G allele had higher serum hs-CRP concentrations, compared with the AA homozygotes, with the wild genotype. Interaction analysis showed the association was modulated by total energy intake; the interaction of high energy intake with GG genotype: RERI= 0.77, AP= 0.26, S=1.6. Conclusion: We have found a significant association between the +1267A>G variant of the HSP70 gene with cardiovascular risk factors and serum hs-CRP concentrations. It is possible that a low energy diet could ameliorate the unfavorable effects of G allele of HSP70

A genetic variant in CDKN2A/2B locus was associated with poor prognosis in patients with 1 esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is among the leading causes of cancer related death. Despite extensive efforts in identifying valid cancer prognostic biomarkers, only a very small number of markers have been identified. Several genetic variants in the 9p21 region have been identified that are associated with the risk of multiple cancers. Here, we explored the association of two genetic variants in the 9p21 region, CDKN2A/B, rs10811661 and rs1333049 for the first time in 273 subjects with, or without ESCC. We observed that patients with ESCC had a higher frequency of a TT genotype for rs10811661 than individuals in the control group, and this polymorphism was also associated with tumor size. Moreover, a CC genotype for the rs1333049 polymorphism was associated with a reduced OS of patients with ESCC. In particular, patients with a CC (rs1333049) genotype had a significantly shorter OS (CC genotype: 34.5±8.9 months vs. CG+GG: 47.7±5.9 months; p value= 0.03). We have also shown the association of a novel genetic variant in CDKN2B gene with clinical outcome of ESCC patients. Further investigations are warranted in a larger population to explore the value of emerging markers as a risk stratification marker in ESCC. Key word: Esophageal squamous cell carcinoma, risk marker, CDKN2A/B, polymorphis

A genetic variant in the cytochrome P450 family 2 subfamily R member 1 determines response to vitamin D supplementation

Background Globally, about 1 billion people have inadequate levels of serum vitamin D and it is prevalent in all ethnicities and age groups. Few foods naturally contain sufficient vitamin D; therefore, most people get their requirements through supplementation. Hence vitamin D status is affected by genetic and environmental determinants including season of measurement, diet habitual, health status, body mass index and concurrent medication. Further studies are necessary to understand how genetic variation influences vitamin D metabolism. We aimed to explore the association between a potential vitamin D-related polymorphism (the rs10766197 polymorphism in the CYP2R1 gene) with the response to supplementation of vitamin D in 253 healthy Iranian girls. Material and method A total of 253 healthy subjects received 50,000 IU of vitamin D3 weekly for 9 weeks. Serum 25(OH)D concentrations and metabolic profiles were measured at baseline and after 9 weeks of supplementation. The genotypes of the CYP2R1 variant (rs10766197) were identified using TaqMan genotyping assays. Results Serum 25(OH)D during the supplementation, increased in all individuals. Subjects with a AA major genotype at this locus had higher vitamin D concentrations after intervention (Changes (%) 448.4% ± 425% in AA vs 382.7% ± 301% in GG). This genetic variant modulated the response to supplementation (p < 0.001 and p-value SNP = 0.05). Regression analysis showed that the probability of affecting serum 25(OH)D, in individuals who had homozygous major allele GG was two-fold higher than carriers of the uncommon allele A (OR = 2.1 (1–4.2); p = 0.03). Interestingly, the Hs-CRP was reduced in AA carries while was elevated in individuals with GG and AG genotypes, after high-dose vitamin D supplementation. Conclusion Changes in serum vitamin D and metabolic profile following high dose supplementation with vitamin D were associated with CYP2R1 polymorphism. Although carriers of the common G allele showed a greater response in the serum vitamin D

Assessing Adherence to Protected Mealtime Guidelines in Iranian Hospitals

Introduction: Malnutrition is a prevalent problem in hospitalized patients, causing a wide range of negative clinical and economic challenges. Protected mealtimes (PM) aim to enhance the quality of mealtime experience, improve nutrient status in hospitalized patients, and limit all non-essential interruptions so that patients might eat in a clean, quiet, and safe environment. Materials and Methods: This study is a clinical audit and was conducted in Mashhad teaching hospitals in order to evaluate mealtime interruptions that occurred among non-nutritional staff and influenced their food intake. Data were collected by direct observation. Lunchtime was chosen for audit because medical interruptions were more likely to happen during this meal. Two researchers (one dietitian, student and one dietetic assistant) observed lunch mealtime. The mealtime environment was monitored, and every negative interruption was registered. Exclusion criteria included patients who were nil-by-mouth or received enteral or parenteral nutrition. Results:A total of 208 patients were involved in the audit. The recorded negative interruptions included medical round, educational round, nurses’ change-of-shift, and activities of environmental service workers. Among interruptions, both medical round and nurses’ change-of-shift were the most frequent. All mealtime interruptions summarized to medical round (2.5%) (including serum replace, drug injection, and IV replace), change-of-shift (2.5%), environmental-service-worker activities (2%), and educational round (2%).  Conclusion: Our study demonstrated that non-urgent interruptions during mealtimes were not adhered to PM guidelines, indicating the importance of addressing mealtime related issues in hospitals

Effect of Ramadan fasting on intra ocular pressure changes in healthy subjects

Introduction: Annually, millions of Muslims all over the world observe the fasting rules based on its measures; this highlights the importance of studies in this field as a worthwhile model for intermittent fasting. It is obvious that changes in lifestyle over fasting have outstanding effects on physiological parameters. The current study was carried out to investigate the IOP and serum electrolytes as two important factors that are influenced by human lifestyle. Methods: Eighty-nine fasting and healthy participants including men and women with mean age of 34.97 were included in our study based on the inclusion and exclusion parameters. During this project, Ramadan coincided with the summer (between June and July 2015). All participants were monitored by an expert examiner and blood samples were collected and IOP was measured by tonometer (Topcon, 1-75, Hasunuma-cho, Itabashi-KU, Tokyo, Japan 2014). The participants were examined one week before and one week after Ramadan. Results: There was a significant reduction in physiological IOP in healthy people after Ramadan. In line with this, the serum electrolytes were altered by fasting so that Na, K, Se experienced a significant decrease while serum phosphorous increased (PConclusion: Prolonged intermittent fasting in Ramadan changed IOP and serum electrolytes in healthy people within a normal range