Dosing Recommendations based on Population Pharmacokinetics of Tacrolimus in Mexican Adult Patients with Kidney Transplant.

Basic Clin Pharmacol Toxicol. 2018 Sep 27;:

Authors: Eduardo RJ, Edith MS, Del Carmen MR, Del Carmen NP, Javier IS, Silvia RM

Abstract
The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in adult Mexican kidney transplant to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one-compartment model and the First-Order Conditional method with Interaction (FOCEI via NONMEM (v.7.3). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of hematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Inter-individual variability associated to tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate stability of the final model; external validation was performed in a new group of patients (n=13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on hematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated. This article is protected by copyright. All rights reserved.

PMID: 30260084 [PubMed - as supplied by publisher]

Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk.

Mol Cancer Res. 2018 Sep 26;:

Authors: Petitalot A, Dardillac E, Jacquet E, Nhiri N, Guirouilh-Barbat J, Julien P, Bouazzaoui I, Bonte D, Feunteun J, Schnell JA, Lafitte P, Aude JC, Nogues C, Rouleau E, Lidereau R, Lopez BS, Zinn-Justin S, Caputo SM

Abstract
BRCA1 mutations have been identified that increase the risk of developing hereditary breast and ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, in order to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected. To better understand the significance of these variants, a high-throughput structural and functional analysis was performed on a large set of BRCA1-VUS. Information on both cellular localization and homology-directed DNA-repair (HR) capacity was obtained for 78 BRCT-missense variants in the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT-domains. This extensive and systematic analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects. A classification is presented based on mutated BRCT-domain solubility, phosphopeptide-binding properties, and VUS HR-capacity. These data suggest that HR-defective variants, which present, in addition, BRCT-domains either insoluble in bacteria or defective for phosphopeptide-binding, lead to an increased cancer risk. Furthermore, the data suggest that variants with a WT HR-activity and whose BRCT-domains bind with a WT affinity to the 5 phosphopeptides are neutral. The case of variants with WT HR-activity and defective phosphopeptide-binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis.

PMID: 30257991 [PubMed - as supplied by publisher]

Impact of Genetic Variability on Physiological Responses to Caffeine in Humans: A Systematic Review.

Nutrients. 2018 Sep 25;10(10):

Authors: Fulton JL, Dinas PC, Carrillo AE, Edsall JR, Ryan EJ, Ryan EJ

Abstract
Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to systematically recognize how select single nucleotide polymorphisms (SNPs) impact habitual use of caffeine as well as the ergogenic and anxiogenic consequences of caffeine. Two databases (PubMed and EBSCO) were independently searched using the same algorithm. Selected studies involved human participants and met at least one of the following inclusion criteria: (a) genetic analysis of individuals who habitually consume caffeine; (b) genetic analysis of individuals who underwent measurements of physical performance with the consumption of caffeine; (c) genetic analysis of individuals who underwent measurements of mood with the consumption of caffeine. We included 26 studies (10 randomized controlled trials, five controlled trials, seven cross-sectional studies, three single-group interventional studies and one case-control study). Single nucleotide polymorphisms in or near the cytochrome P450 (CYP1A2) and aryl hydrocarbon receptor (AHR) genes were consistently associated with caffeine consumption. Several studies demonstrated that the anxiogenic consequences of caffeine differed across adenosine 2a receptor (ADORA2A) genotypes, and the studies that investigated the effects of genetic variation on the ergogenic benefit of caffeine reported equivocal findings (CYP1A2) or warrant replication (ADORA2A).

PMID: 30257492 [PubMed - in process]

Gene isoforms as expression-based biomarkers predictive of drug response in vitro.

Nat Commun. 2017 10 24;8(1):1126

Authors: Safikhani Z, Smirnov P, Thu KL, Silvester J, El-Hachem N, Quevedo R, Lupien M, Mak TW, Cescon D, Haibe-Kains B

Abstract
Next-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.

PMID: 29066719 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/26

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Combined Albendazole and Praziquantel Therapy in an Adult Female with Neurocysticercosis and Generalized Tonic-clonic Seizures.

Cureus. 2018 Jul 18;10(7):e2996

Authors: Petrov K, Ihongbe F, Chang M, Choudhary S, Bhatia D

Abstract
The use of albendazole monotherapy has been favored as the treatment option for neurocysticercosis. This case reports an incidence of neurocysticercosis in a 32-year-old woman who presented to the emergency department with a generalized tonic-clonic seizure. Neurocysticercosis was confirmed by magnetic resonance imaging (MRI) of the brain and a positive Taenia solium serologic test. The patient was treated with the combined dual therapy of albendazole and praziquantel at standard doses for a minimum effective duration of 14 days in the setting of scarce patient resources. She tolerated therapy without any adverse reactions and remained seizure free. A repeat MRI scan post-treatment revealed the complete eradication of cysticerci. Clinicians should be aware of and consider the efficacy and safety of combined albendazole and praziquantel therapy for the treatment of neurocysticercosis.

PMID: 30245950 [PubMed]

In silico Prioritization of Transporter-Drug Relationships From Drug Sensitivity Screens.

Front Pharmacol. 2018;9:1011

Authors: César-Razquin A, Girardi E, Yang M, Brehme M, Saez-Rodriguez J, Superti-Furga G

Abstract
The interplay between drugs and cell metabolism is a key factor in determining both compound potency and toxicity. In particular, how and to what extent transmembrane transporters affect drug uptake and disposition is currently only partially understood. Most transporter proteins belong to two protein families: the ATP-Binding Cassette (ABC) transporter family, whose members are often involved in xenobiotic efflux and drug resistance, and the large and heterogeneous family of solute carriers (SLCs). We recently argued that SLCs are collectively a rather neglected gene group, with most of its members still poorly characterized, and thus likely to include many yet-to-be-discovered associations with drugs. We searched publicly available resources and literature to define the currently known set of drugs transported by ABCs or SLCs, which involved ∼500 drugs and more than 100 transporters. In order to extend this set, we then mined the largest publicly available pharmacogenomics dataset, which involves approximately 1,000 molecularly annotated cancer cell lines and their response to 265 anti-cancer compounds, and used regularized linear regression models (Elastic Net, LASSO) to predict drug responses based on SLC and ABC data (expression levels, SNVs, CNVs). The most predictive models included both known and previously unidentified associations between drugs and transporters. To our knowledge, this represents the first application of regularized linear regression to this set of genes, providing an extensive prioritization of potentially pharmacologically interesting interactions.

PMID: 30245630 [PubMed]

Adverse Drug Reactions Across the Age Continuum: Epidemiology, Diagnostic Challenges, Prevention, and Treatments.

J Clin Pharmacol. 2018 Oct;58 Suppl 10:S36-S47

Authors: Rieder M

Abstract
Adverse drug reactions (ADRs) are common and important complications of drug therapy for children. The risk for ADRs changes over childhood, as do the nature and types of ADRs. Importantly, the risk and nature of ADRs in children are markedly different from those of adults, and adult data cannot be relied on to guide safe drug therapy in children. There are groups of children, notably those with complex and chronic diseases, who are at substantial risk for ADRs. The evaluation of an undesired effect during therapy is ideally accomplished by an organized approach that is a skill that clinicians who care for children-especially those children at high risk for ADRs must have. Additionally, clinicians as well as drug regulatory agencies and industry need to be both vigilant and astute as well as aware that ADRs in children are often different in nature and frequency from those in adults. The increasing use of pharmacogenomics to guide drug dosing and the increasing number of biological agents will provide new sets of challenges to clinicians over the next decade.

PMID: 30248196 [PubMed - in process]

Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice.

Biol Pharm Bull. 2018;41(5):707-712

Authors: Yi-Wen Z, Mei-Hua B, Xiao-Ya L, Yu C, Jing Y, Hong-Hao Z

Abstract
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as dietary supplement or therapeutic drug, while the effects of oridonin on CYP450 were still unclear. The pregnane X receptor (PXR) is an important regulatory factor for major drug metabolism enzyme CYPs, and it has been reported to have species-specific differences. Therefore, this study has employed more reliable models PXR-humanized mouse to investigate the influence of oridonin on PXR and downstream metabolism enzyme. Eight-week-old male PXR-humanized mice were treated with oridonin by orally (0, 25, 50, 100, 200 mg/kg) for 15 d. The effects of oridonin on major downstream CYPs of PXR were examined at both the mRNA and enzyme activity levels by RT-PCR and HPLC-MS/MS. In general, there was no significant toxic reaction in liver of PXR-humanized mice. The mRNA expression of CYPs and cytochrome P450 oxidoreductase (POR) were increased with oridonin treatment in a dose-dependent manner. CYP2c and CYP3a family catalytic activity were increased significantly in two higher doses groups. These results indicate that oridonin induced the expression and activation of CYP2c and CYP3a family, which might contribute to potential drug-drug interactions and appear to be a risk when co-administered with other clinical drugs.

PMID: 29709908 [PubMed - indexed for MEDLINE]

Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population.

Int J Neurosci. 2018 Aug;128(8):705-714

Authors: Ajmi M, Boujaafar S, Zouari N, Amor D, Nasr A, Rejeb NB, Amor SB, Omezzine A, Benammou S, Bouslama A

Abstract
PURPOSE: We aimed in this study to investigate the association between the ATP-Binding Cassette sub-family B, member1 (ABCB1) polymorphisms: C1236T (rs1128503), G2677T (rs2032582) and C3435T (rs1045642), and the resistance to antiepileptic drugs (AEDs).
MATERIALS AND METHODS: The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping of ABCB1 polymorphisms was conducted on 153 Tunisian epileptic patients treated with AEDs.
RESULTS: Two genetic polymorphisms of the ABCB1 gene seemed to influence the response to AEDs. In fact, the G2677T T and the C3435T T alleles appeared to increase the risk of developing AEDs resistance (ORs* = 3.13; 95%CI = [1.16-8.98]; p = 0.024 and ORs* = 3.10; 95%CI = [1.15-8.37]; p = 0.025), respectively. However, the C1236T T allele did not seemed to influence the response to AEDs (ORs* = 1.14; 95%CI = [0.53-3.88]; p = 0.471). Haplotypic analysis indicated high-degree linkage disequilibrium of ABCB1 polymorphisms. Our results showed a synergic effect, in fact patients with the CTT and TTT haplotypes were more likely to be drug resistant than patients with the CGC haplotype, these associations remained significant even after adjustment for confounding parameters (ORs* = 2.68; 95%CI = [1.11-8.25]; p = 0.033 and ORs* = 3.76; 95%CI = [1.69-21.05]; p = 0.006, respectively).
CONCLUSION: The G2677T T and C3435T T alleles as well as the TT, CTT and TTT haplotypes seemed to be significantly associated with drug-resistance epilepsy in our population. Genetic predisposition, involved in this resistance, may contribute to the establishment of a personal optimized therapy for newly diagnosed epileptic patients.

PMID: 29198163 [PubMed - indexed for MEDLINE]

Barriers to medication adherence and links to cardiovascular disease risk factor control: the Framingham Heart Study.

Intern Med J. 2018 04;48(4):414-421

Authors: Hennein R, Hwang SJ, Au R, Levy D, Muntner P, Fox CS, Ma J

Abstract
BACKGROUND: In the elderly, impaired cognition may weaken medication adherence and compromise treatment for cardiovascular disease (CVD).
AIM: We examined risk factors for medication adherence and the relationship between adherence and levels of CVD risk factors among older participants with hypertension, dyslipidaemia and diabetes in the Framingham Heart Study.
METHODS: The four-item Morisky Medication Adherence Scale was administered to 1559 participants, median age 70 years, 53% women. We created an adherence score, ranging from 0 to 4, with low adherence defined as a score ≥2. CVD risk factors were assessed using standard protocols. Cognition was measured using the Mini-Mental State Examination (MMSE) and depressive symptoms were measured using the Center for Epidemiologic Studies of Depression (CES-D) scale.
RESULTS: Among participants who self-reported taking antihypertensive, lipid-lowering and/or hyperglycaemic medication(s), 12% (n = 191) had low medication adherence. The risk of low adherence increased by 45% (95% confidence interval (CI): 25-68%, P < 0.001) per five-unit increase in CES-D score. In participants taking antihypertensive medication (n = 1017), low adherence was associated with higher mean diastolic blood pressure (73 mmHg, 95% CI: 71-75 vs 71 mmHg, 95% CI: 70-71; P = 0.04) after adjusting for covariates. Among participants taking lipid-lowering medication (n = 937), low adherence was associated with higher mean low-density lipoprotein cholesterol (92 mg/dL, 95% CI: 87-96 vs 86 mg/dL, 95% CI: 84-88; P = 0.03). Low adherence was not associated with fasting plasma glucose (P = 0.10) or haemoglobin A1c (P = 0.68) in the subgroup of participants (n = 192) taking hypoglycaemic medication.
CONCLUSIONS: Depressive symptoms might act as a barrier for medication adherence, which exacerbates CVD risk factors in older-aged adults.

PMID: 29193523 [PubMed - indexed for MEDLINE]

Future prospect of faecal microbiota transplantation as a potential therapy in asthma.

Allergol Immunopathol (Madr). 2018 May - Jun;46(3):307-309

Authors: Kang Y, Cai Y

Abstract
There is convincing evidence from both human and animal studies suggesting that the gut microbiota plays an important role in regulating immune responses associated with the development of asthma. Certain intestinal microbial strains have been demonstrated to suppress or impair immune responsiveness in asthma experimental models, suggesting that specific species among gut commensal microbiota may play either a morbific or phylactic role in the progression of asthma. Evidence to date suggests that the intestinal microbiota represent fertile targets for prevention or management of asthma. The faecal microbiota transplantation (FMT) is a rather straightforward therapy that manipulates the human gastrointestinal (GI) microbiota, by which a healthy donor microbiota is transferred into an existing but disturbed microbial ecosystem. The FMT may therefore represent a therapeutic approach for asthma treatment in the foreseeable future. At present, FMT therapy for asthma is very limited and should be actively studied. Considerable efforts are needed to increase our knowledge in the field of FMT therapy for asthma. In this review, we aimed to provide several insights into the development of FMT therapy for asthma.

PMID: 28803667 [PubMed - indexed for MEDLINE]

Mass isotopomer-guided decluttering of metabolomic data to visualize endogenous biomarkers of drug toxicity.

Biochem Pharmacol. 2018 Sep 19;:

Authors: Beyoğlu D, Zhou Y, Chen C, Idle JR

Abstract
Metabolomics offers the opportunity to uncover endogenous biomarkers that can lead to metabolic pathways and networks and that underpin drug toxicity mechanisms. A novel protocol is presented and discussed that is applicable to drugs which generate urinary metabolites when administered to mice sensitive to its toxicity. The protocol would not apply to drugs that are not metabolized or eliminated by a different route. Separate stable isotope-labeled and unlabeled drug administration to mice is made together with collection of urines from control animals. Untargeted mass spectrometry-based metabolomic analysis of these three urine groups is conducted in addition to principal components analysis (PCA). In the case of unlabeled acetaminophen and [acetyl-2H3]acetaminophen, each given at a hepatotoxic dose (400 mg/kg i.p.) to the sensitive mouse strain (wild-type 129), the PCA loadings plot showed a distribution of ions in the shape of a "fallen-Y" with the deuterated metabolites in one arm and the paired nondeuterated metabolites in the other arm of the fallen-Y. Ions corresponding to the endogenous toxicity biomarkers sat in the mouth of the fallen-Y. This protocol represents an innovative means to separate endogenous biomarkers from drug metabolites, thereby aiding the identification of biomarkers of drug toxicity. For acetaminophen, increased hepatic oxidative stress, mitochondrial damage, Ca2+ signaling, heme catabolism, and saturation of glucuronidation, together with decreased fatty acid β-oxidation and cellular energy dysregulation were all implied from the discovered biomarkers. The protocol can be applied to other drugs and may now be translated to clinical studies.

PMID: 30243960 [PubMed - as supplied by publisher]

[The serotonin syndrome: An updated literature review].

Rev Med Interne. 2018 Sep 19;:

Authors: Jurek L, Nourredine M, Megarbane B, d'Amato T, Dorey JM, Rolland B

Abstract
The serotonin syndrome is a potentially deadly complication resulting from drug adverse effect, drug-drug interaction or overdose involving one or more serotonergic molecules, e.g., antidepressants, psychostimulants and sometimes an "ignored" serotonergic compound. The serotonin syndrome typically consists of a clinical triad including cognitive/behavioral, neurovegetative and neuromuscular features. However, this syndrome is characterized by major clinical heterogeneity, making the diagnosis difficult in practice. Moreover, many practitioners are quite unaware of this syndrome. Available scores and classifications can help physicians in their diagnosis approach. Knowing the responsible molecules, their potential interactions and mechanisms of action can help preventing this complication allowing therapeutic education among patients. This updated article reviews the clinical presentation, prevention, management, and pathophysiology of the serotonin syndrome, and addresses the most recent advances in pharmacogenetics regarding this syndrome.

PMID: 30243558 [PubMed - as supplied by publisher]

MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion.

Endocrine. 2018 Sep 21;:

Authors: Chen ZR, He FZ, Liu MZ, Hu JL, Xu H, Zhou HH, Zhang W

Abstract
PURPOSE: Diabetes mellitus is a major chronic disease and causes over one million deaths. KCNJ11 genetic polymorphisms influence the response of first-line oral antidiabetic agent sulfonylureas. Hsa-miR-4532 correlates with diabetic nephropathy and has a high abundance in urine. MIR4532 rs60452575 G>A variant changes the mature sequence of hsa-miR-4532. We studied whether the genetic polymorphisms of MIR4532 rs60452575 would influence KCNJ11 expression and sulfonylurea-stimulated insulin secretion or not.
METHODS: To estimate the influence that rs60452575 G>A variant has on the interaction of hsa-miR-4532 and KCNJ11, we constructed a pmirGLO vector containing 3' UTR of KCNJ11 and co-transfected it with wild-type and mutant hsa-miR-4532 mimics into HEK293 cells; and we overexpressed wild-type and mutant hsa-miR-4532 mimics into HEK293 cells and MIN6 cells to access its effects on KCNJ11 expression and response of sulfonylureas.
RESULTS: MIR4532 rs60452575 G>A variant appeared to disrupt the repression of KCNJ11 expression in both cell lines, and reduce the sulfonylurea-stimulated insulin secretion by breaking the binding of the hsa-miR-4532 to 3' UTR of KCNJ11 in MIN6 cells.
CONCLUSIONS: Our study indicates that MIR4532 rs60452575 variant influences KCNJ11 expression and sulfonylurea response. It might be a potential predictive factor of sulfonylureas therapy.

PMID: 30242599 [PubMed - as supplied by publisher]

Association between HLA-B*5901 and methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis.

Pharmacogenomics J. 2018 Sep 21;:

Authors: Tangamornsuksan W, Lohitnavy M

Abstract
Methazolamide-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life-threatening adverse drug reactions. Based on previous studies, HLA genotypes may play an important role in methazolamide-induced SJS/TEN. Therefore, to identify the associations between HLA genotypes and methazolamide-induced cutaneous adverse drug reactions (cADRs) (i.e., SJS/TEN and hypersensitivity syndrome), a systematic review and meta-analysis were performed. Two studies (one study in Korean and another in Han Chinese) met the inclusion criteria. The studies included 13 patients with methazolamide-induced SJS/TEN, 30 methazolamide-tolerant, and 768 population controls. Associations between HLA-B*5901, HLA-B*5901-Cw*0102 haplotype, and methazolamide-induced SJS/TEN were identified in methazolamide-tolerant and population controls. Overall ORs were 305.0 (95% CI = 11.3-8, 259.4) in methazolamide-tolerant and 715.3 (95% CI = 83.1-6,158.5) in population control. In addition, statistically significant associations between the HLA-Cw*0102 and methazolamide-induced SJS/TEN were found in methazolamide-tolerant (OR = 12.1; 95% CI = 1.3-111.7) and population control (OR = 17.5; 95% CI = 3.2-96.6). Since HLA-B*5901 and HLA-B*5901-Cw*0102 haplotype are associated with methazolamide-induced SJS/TEN, genetic screening prior to methazolamide therapy in Asian populations is warranted.

PMID: 30242287 [PubMed - as supplied by publisher]

Konjaku flour reduces obesity in mice by modulating the composition of the gut microbiota.

Int J Obes (Lond). 2018 Sep 21;:

Authors: Kang Y, Li Y, Du Y, Guo L, Chen M, Huang X, Yang F, Hong J, Kong X

Abstract
BACKGROUND: Changes in the intestinal flora composition is referred to as dysbiosis, which is related to obesity development, thus supporting the potential roles of nutrients acting on intestinal flora to exert salutary effects on energetic metabolism of host. Dietary fiber has been known to affect the composition of intestinal flora. The aim of the present study was to investigate the functional effects of konjac flour (KF) on obesity control in respect to improving inflammation, metabolism, and intestinal barrier function, and the possible association of the effects with intestinal flora composition changes.
METHODS: Mice (n = 30) were randomly divided into control group (n = 10), high-fat-diet (HFD) group (n = 10), and KF intervention group (n = 10), followed by feeding for 12 weeks and with adding a KF daily supplementation for the treatment group. Body weight, fat accumulation, inflammation, and energetic metabolism markers in multiple tissues and the gut microbiota of the mice were examined at the end of the experiment.
RESULTS: The KF supplementation significantly reduced the gains in weight, fat mass, as well as adipocyte size of HFD mice and lowered the serum TC, leptin (LEP), thiobarbituric acid-reacting substance (TBARS), IL-6, and lipopolysaccharide (LPS) levels in HFD mice. KF also upregulated the expression of intestinal mucosa protein gene Intection and tight junction ZO-1 in HFD mice, as well as upregulate the expression of energy metabolism genes PPARα and CPT-1 as well as the fat metabolism gene HLS in livers and fat tissues, and downregulate that of fat synthesis gene PPARγ (p < 0.05). The KF treatment increases the α-diversity and change the β-diversity of the intestinal microflora in HFD mice and boosted the abundances of some obesity-related beneficial microorganisms (such as Megasphaera elsdenii) in the intestinal microflora of HFD mice, while reduced those of harmful microorganisms (such as Alistipes, Alloprevotella, Bacteroides acidifaciens, and Parabacteroides goldsteinii). The abundance of Alistipes was positively correlated with weight, fat mass, serum TC, TG, LEP, IL-6, and LPS contents as well as PPARγ gene expression; while notably and negatively related to the expression of CPT-1 and HLS genes (p < 0.01). KF remarkably increased the abundance of Aerococcaceae, while reduced that of Alistipes finegoldii (p < 0.01).
CONCLUSIONS: Supplementation with KF achieves favorable effects on treating obesity, improving inflammatory response, metabolism, and intestinal barrier function, by regulating intestinal microfloral structure in HFD-fed mice.

PMID: 30242233 [PubMed - as supplied by publisher]

Biomarkers of dementia in obstructive sleep apnea.

Sleep Med Rev. 2018 Aug 13;:

Authors: Baril AA, Carrier J, Lafrenière A, Warby S, Poirier J, Osorio RS, Ayas N, Dubé MP, Petit D, Gosselin N, Canadian Sleep and Circadian Network

Abstract
Epidemiologic and mechanistic evidence is increasingly supporting the notion that obstructive sleep apnea is a risk factor for dementia. Hence, the identification of patients at risk of cognitive decline due to obstructive sleep apnea may significantly improve preventive strategies and treatment decision-making. Cerebrospinal fluid and blood biomarkers obtained through genomic, proteomic and metabolomic approaches are improving the ability to predict incident dementia. Therefore, fluid biomarkers have the potential to predict vulnerability to neurodegeneration in individuals with obstructive sleep apnea, as well as deepen our understanding of pathophysiological processes linking obstructive sleep apnea and dementia. Many fluid biomarkers linked to Alzheimer's disease and vascular dementia show abnormal levels in individuals with obstructive sleep apnea, suggesting that these conditions share common underlying mechanisms, including amyloid and tau protein neuropathology, inflammation, oxidative stress, and metabolic disturbances. Markers of these processes include amyloid-β, tau proteins, inflammatory cytokines, acute-phase proteins, antioxydants and oxidized products, homocysteine and clusterin (apolipoprotein J). Thus, these biomarkers may have the ability to identify adults with obstructive sleep apnea at high risk of dementia and provide an opportunity for therapeutic intervention. Large cohort studies are necessary to establish a specific fluid biomarker panel linking obstructive sleep apnea to dementia risk.

PMID: 30241998 [PubMed - as supplied by publisher]