Ranking the dietary interventions by their effectiveness in the management of polycystic ovary syndrome: a systematic review and network meta-analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common condition in women, characterised by reproductive and metabolic dysfunction. While dietary approaches have been evaluated as a first-line treatment for patients with PCOS, there is limited evidence to support preference for a specific dietary composition. This systematic review and network meta-analysis was performed with the objective of comparing different dietary interventions in terms of positive impact. Metformin, the currently preferred treatment, was also compared. METHODS: The latest systematic search was performed on the 20th of March, 2023. Eligible randomised controlled trials (RCTs) included patients with PCOS and compared the dietary approach with another intervention or a standard diet. Outcomes were expressed via anthropometric measurements and hormonal, glycemic, and lipid levels. The Bayesian method was used to perform a network meta-analysis and to calculate the surface under the cumulative ranking curve (SUCRA) values in order to rank the dietary interventions. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: 19 RCTs were identified, comprising data from 727 patients who were variously treated with 10 types of dietary interventions and metformin. The Dietary Approaches to Stop Hypertension (DASH) diet was the most effective in reducing Homeostatic Model Assessment of Insulin Resistance (SUCRA 92.33%), fasting blood glucose (SUCRA 85.92%), fasting insulin level (SUCRA 79.73%) and triglyceride level (SUCRA 82.07%). For body mass index (BMI), the most effective intervention was the low-calorie diet (SUCRA 84.59%). For weight loss, the low-calorie diet with metformin (SUCRA 74.38%) was the most effective intervention. Metformin produced the greatest reductions in low-density lipoprotein cholesterol (SUCRA 78.08%) and total testosterone levels (SUCRA 71.28%). The low-carb diet was the most effective intervention for reducing cholesterol levels (SUCRA 69.68%), while the normal diet (SUCRA 65.69%) ranked first for increasing high-density lipoprotein cholesterol levels. CONCLUSION: Dietary interventions vary in their effects on metabolic parameters in women with PCOS. Based on our results, the DASH diet is the most effective dietary intervention for treating PCOS. Registration PROSPERO ID CRD42021282984.

Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Metformin is the gold standard insulin sensitizer, which is widely used to treat insulin resistance in polycystic ovary syndrome (PCOS). However, metformin may induce gastrointestinal side effects. OBJECTIVE: Inositols have long been debated as a potential alternative for metformin in treating PCOS. Therefore, the present systematic review aimed to evaluate the efficacy and safety of inositols in treating PCOS. METHODS: The present systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. Our primary outcome was cycle normalization, whereas secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism and clinical and laboratory hyperandrogenism. Results are reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). In patients treated with inositols, the risk (CI: 1.13; 2.85) of having a regular menstrual cycle was found by 1.79 higher than in the case of placebo. Moreover, the inositols showed non-inferiority compared to metformin in this outcome. In the case of BMI (MD = -0.45; CI: -0.89; -0.02), free testosterone (MD = -0,41, CI: -0.69; -0.13), total testosterone (MD = -20.39, CI: -40.12; -0.66), androstenedione (MD = -0.69, CI: -1,16; -0.22), glucose (MD = -3.14; CI: -5.75; -0.54) levels and AUC insulin (MD = -2081.05, CI: -2745.32; -1416.78) inositol treatment induced greater decrease compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo (MD = 32.06, CI:1.27; 62.85). CONCLUSION: Inositol is an effective and safe treatment in PCOS. Moreover, inositols showed non-inferiority in most outcomes compared to the gold standard treatment; metformin. TRIAL REGISTRATION: PROSPERO registration number: CRD42021283275.

New Metabolic Influencer on Oxytocin Release: The Ghrelin.

BACKGROUND: The hypothalamic⁻pituitary axis by secreting neuropeptides plays a key role in metabolic homeostasis. In light of the metabolic regulation, oxytocin is a potential neuropeptide for therapies against obesity and related disorders. The aim of our study is to measure ghrelin-induced oxytocin secretion in rats and to detect the changes after administration of ghrelin antagonist. METHODS: Ghrelin was administrated centrally (intracerebroventricular, i.c.v., 1.0, 10.0, and 100.0 pmol) or systemically (intravenous, i.v., 1.0, and 10.0 nmol). [d-Lys³]-GHRP-6 ghrelin antagonist was injected 15 min before ghrelin injection in a dose of 10.0 pmol i.c.v. and 10.0 nmol i.v. RESULTS: Either i.c.v. or i.v. administration of ghrelin dose-dependently increased the plasma oxytocin concentration. Following pretreatment with the ghrelin antagonist [d-Lys³]-GHRP-6, the high plasma oxytocin level induced by ghrelin was significantly reduced. CONCLUSION: The results indicate that the release of oxytocin is influenced directly by the ghrelin system. Examination of the mechanism of ghrelin-induced oxytocin secretion is a new horizon for potential therapeutic options.

Galactomannans are the most effective soluble dietary fibers in type 2 diabetes: a systematic review and network meta-analysis.

BACKGROUND: Soluble dietary fibers are known to reduce the levels of blood glucose and lipids in patients with type 2 diabetes mellitus (type 2 diabetes). Although several different dietary fiber supplements are utilized, to our knowledge, no previous study has ranked their efficacy yet. OBJECTIVES: We performed this systematic review and network meta-analysis to rank the effects of different types of soluble dietary fibers. METHODS: We performed our last systematic search on November 20, 2022. Eligible randomized controlled trials (RCTs) included adult patients with type 2 diabetes and compared the intake of soluble dietary fibers with that of another type of dietary fiber or no fiber. The outcomes were related to glycemic and lipid levels. The Bayesian method was used to perform a network meta-analysis and calculate the surface under the cumulative ranking (SUCRA) curve values to rank the interventions. The Grading of Recommendations Assessment, Development, and Evaluation system was applied to evaluate the overall quality of the evidence. RESULTS: We identified 46 RCTs, including data from 2685 patients who received 16 types of dietary fibers as intervention. Galactomannans had the highest effect on reducing the levels of HbA1c (SUCRA: 92.33%) and fasting blood glucose (SUCRA: 85.92%). With regard to fasting insulin level, HOMA-IR, ß-glucans (SUCRA: 73.45%), and psyllium (SUCRA: 96.67%) were the most effective interventions. Galactomannans were ranked first in reducing the levels of triglycerides (SUCRA: 82.77%) and LDL cholesterol (SUCRA: 86.56%). With regard to cholesterol and HDL cholesterol levels, xylo-oligosaccharides (SUCRA: 84.59%) and gum arabic (SUCRA: 89.06%) were the most effective fibers. Most comparisons had a low or moderate certainty of evidence. CONCLUSIONS: Galactomannans were the most effective dietary fiber for reducing the levels of HbA1c, fasting blood glucose, triglycerides, and LDL cholesterol in patients with type 2 diabetes. This study was registered at PROSPERO as ID CRD42021282984.

[Achetylcholinesterase (AChE) inhibition and serum lipokines in Alzheimer's disease: friend or foe?]. / Acetilkolin-észteráz gátlás és szérum lipokinek Alzheimer-kórban: barát vagy ellenség?

Throughout the natural progression of Alzheimer's disease (AD), the body mass index (BMI) decreases. This is believed to be brought on by the disturbance in the central lipid metabolism, but the exact mechanism is yet unknown. Adipokines (adiponectin, leptin), hormones produced by the adipose tissue, change glucose and lipid metabolism, and have an anorectic effect through increasing energy consumption in the hypothalamus. The goal of our study was to examine donepezil - an acetylcholinesterase inhibitor (AChEI) currently used in AD therapy -, and to what degree it influences the serum adipokine levels and metabolic parameters of AD patients. During the self-evaluation of 26 clinically diagnosed mild to moderate AD patients, therapy with 10 mg/day donepezil was started according to current protocols. We measured serum adiponectin, leptin, LDL, HDL, trigliceride levels, and BMI and ApoE polymorphism at the beginning of our study, and at 3 and 6-months intervals respectively. All data were analyzed with SPSS 17. In comparison with pre-donepezil therapy values, at the third month interval serum adiponectin levels showed an increasing and leptin levels a decreasing tendency. At the six month interval, adiponectin levels significantly increased (p=0.007), leptin levels decreased (p=0.013), BMI (p=0.001) and abdominal circumference (p=0.017) was significantly lower at 6 months as compared to control values. We did not observe any changes in the lipid profile, and ApoE4 allele carrying showed no association with the parameters. To our knowledge, we are the first to publish that AChEI therapy with donepezil alters lipokine levels, which positively influences the currently known pathomechanism and numerous risk factors of AD. The AChEI treatment-induced weight loss should be considered in the long-term therapy of AD patients.

Tau haplotypes and ApoE4 do not act in synergy on Alzheimer's disease.

There are conflicting results regarding the role of tau (MAPT) haplotypes in neurodegenerative disorders. Recent reports suggest that ethnicity factors and gene-gene interactions may influence the risk of developing Alzheimer's disease (AD). The present study investigates possible synergism between MAPT haplotype and ApoE state in Hungarian Caucasian AD cases (n=91) and control (n=83) population. The difference in MAPT H1 allele frequency did not reach significant level in AD (78%), and control individuals (73.5%), however ApoE4 carriers were significantly overrepresented in AD (34.1% vs. 20%) compared to the control population. Though a specific combination of ApoE4 and H1 alleles were found to be associated to AD (14.5% vs. 30.8%), synergistic genetic interaction could not be inferred. Our findings support the notion that while ApoE4 might be involved in AD pathology the MAPT H1 allele neither associates nor interacts through an epistasis with ApoE4 in the development of the disease.

Association study of interferon-γ, cytosolic phospholipase A2, and cyclooxygenase-2 gene polymorphisms in Alzheimer disease.

OBJECTIVE: The increased production of proinflammatory mediators such as cytokines and prostaglandins may interact at multiple levels with neurodegeneration in Alzheimer disease (AD). This study was undertaken to evaluate the possible role of interferon-γ (IFN-γ) T+874A, cytoplasmic phospholipase A2 (cPLA2) BanI, and cyclooxygenase-2 (COX-2) G-765C polymorphisms in AD. METHODS: The study included 237 probable patients with AD who met the diagnostic criteria of National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association, and 245 probands in the healthy comparison (HC) group. RESULTS: No significant difference in mean age or in the distribution of genders between AD and HC groups was found. The COX-2 G/G genotype was significantly more frequent in the AD, when compared with the HC group. There was no significant correlation between IFN-γ or cPLA2 genotypes and AD. CONCLUSIONS: Our findings indicate that the COX-2 G/G genotype is associated with AD and support the involvement of COX-2 in AD etiology.

Association between a genetic variant of the alpha-7 nicotinic acetylcholine receptor subunit and four types of dementia.

We tested the hypothesis whether the partially duplicated variant of alpha7 nicotinic acetylcholine receptor subunit gene (CHRFAM7A) 2-bp deletion (-2 bp) polymorphism and apolipoprotein E (ApoE) epsilon4 allele confer susceptibility to Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Pick's disease (PiD) and vascular dementia (VD). The study included 175 AD, 35 DLB patients, 38 PiD, 96 VD and 175 healthy control (HC) probands. The CHRFAM7A genotype without the -2 bp allele was significantly over-represented in AD (p = 0.011), DLB (p = 0.001) and PiD (p < 0.0001) compared to HC, but there were no statistical differences in VD (p = 0.407) compared to HC. We confirmed again that the ApoE epsilon4 allele is a risk factor for dementias. The -2 bp polymorphism of CHRFAM7A can be implicated in AD, DLB and PiD. However, it is unlikely that it plays an important role in the pathogenesis of VD.

Association between BDNF Val66Met polymorphism and Alzheimer disease, dementia with Lewy bodies, and Pick disease.

A functional polymorphism of the brain-derived neurotrophic factor (BDNF Val66Met) has been reported to affect memory-related hippocampal activity. Apolipoprotein E (ApoE) gene polymorphism is known to be associated with Alzheimer disease (AD), dementia with Lewy bodies (DLB), and Pick disease (PiD). We tested the hypothesis that BDNF Val and ApoE epsilon4 alleles confer susceptibility to AD, DLB, and PiD. The study included 160 AD, 34 DLB patients, 38 autopsy-confirmed PiD, and 164 age-matched healthy control (HC) probands. The frequency of the BDNF Val allele was significantly higher in AD, but there were no statistical differences in the allele distribution in PiD or in DLB as compared with HC. The Val/Met genotype occurred with statistically significantly higher frequency in PiD than in HC. The ApoE epsilon4 allele was significantly overrepresented in all dementias as compared with HC. Genotypes containing both ApoE epsilon4 and BDNF Val alleles occurred more frequently in all investigated dementias than in HC. We suggest that the presence of the BDNF Val allele in itself and in combination with the ApoE epsilon4 allele can be risk factors for AD, and the results indicate a synergistic effect of the 2 polymorphisms on DLB and PiD risk.

Association study of the ABCA7 rs3752246 polymorphism in Alzheimer's disease.

The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene has been identified as a strong genetic risk locus for Alzheimer's disease (AD). Our case-control study (416 AD patients and 302 controls) provides further data on the rs3752246 polymorphism in AD in the Hungarian population that has not been investigated so far regarding the ABCA7 gene variants. A modest, marginally significant association of the G allele containing genotypes with AD was observed (p = 0.054). In line with the previous results in other populations, the G allele carriers had an increased risk for developing AD considering C/C genotype as reference category.

ABCA1 rs2230805 and rs2230806 common gene variants are associated with Alzheimer's disease.

The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a relevant positional and functional candidate gene for Alzheimer's disease (AD). A case-control association study of genetic variations covering the ABCA1 locus was performed in relation to AD risk in a Hungarian sample. Five single nucleotide polymorphisms (rs2422493: C-477T, rs2740483: G-17C, rs2230805: G474A/L158L, rs2230806: G656A/R219K and rs2066718: G2311A/V771M) were genotyped in 431 AD patients and 302 cognitively healthy, elderly controls. In single marker analysis, significant associations were found in the case of rs2230805 and rs2230806 polymorphisms: the minor A allele containing genotypes for both polymorphisms were more frequent in the control compared to the AD group. Haplotype analysis revealed that rs2230805, rs2230806 and rs2066718 polymorphisms created a linkage disequilibrium (LD) block with a strong LD between rs2230805 and rs2230806 polymorphisms. In the haplotype risk association tests, A-A-G haplotype of the rs2230805-rs2230806-rs2066718 polymorphisms was found to be nominally significantly more frequent in the control group. After correcting p values for multiple testing, only the effects of the rs2230805 and rs2230806 polymorphisms remained significant in the recessive model suggesting a modest protective effect of their minor alleles in AD, which should be interpreted with considerable caution, until further studies elucidate their role in AD pathology.

APP mRNA splicing is upregulated in the brain of biglycan transgenic mice.

Many of the risk factors for cerebrovascular disease and atherosclerosis also increase the risk of Alzheimer's disease, characterized by the cerebral deposition of beta-amyloid plaques resulting from the abnormal processing of the transmembrane amyloid precursor protein (APP). The initiating event of cholesterol-induced atherosclerosis is the retention and accumulation of atherogenic apolipoprotein B (apoB) together with low-density lipoproteins in the vascular intima. Biglycan, a member of the small leucine-rich protein family, was suspected of contributing to this process. The individual and combined overexpressions of biglycan and apoB-100 were therefore examined on the cortical APP mRNA levels of transgenic mice by means of semiquantitative PCR. As compared with the control littermates, transgenic biglycan mice had significantly increased cortical APP695 (122%) and APP770 (157%) mRNA levels, while the double transgenic (apoB(+/-)xbiglycan(+/-)) mice did not exhibit any changes. These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias.

Decreased serum and red blood cell kynurenic acid levels in Alzheimer's disease.

Kynurenine aminotransferases (KAT I and KAT II) are responsible for the transamination of kynurenine (KYN) to form kynurenic acid (KYNA), an excitatory amino acid receptor antagonist. Since these members of the kynurenine pathway (KP) are proposed to be involved in the pathogenesis of Alzheimer's dementia (AD), the activities of these enzymes and the levels of these metabolites were measured in the plasma and red blood cells (RBCs) of AD and control subjects together with the inheritance of the apolipoprotein (APOE) epsilon4 allele. KYNA levels were significantly decreased both in the plasma and in the RBCs in AD, but the levels of KYN and the activities of KAT I and KAT II remained unchanged. No association has been found with the possession of the epsilon4 allele. These findings indicate an altered peripheral KP in AD regardless of the APOE status of the probands.

Major depressive disorder, serotonin transporter, and personality traits: why patients use suboptimal decision-making strategies?

BACKGROUND: Patients with major depressive disorder (MDD) show suboptimal decision-making strategy in experimental game situations. The influence of personality traits and genetic variations on decision-making is not known. METHODS: Contingency learning based on the cumulative effect of reward and punishment was assessed in 124 patients with unipolar MDD using the ABCD (reward sensitivity) and EFGH (punishment sensitivity) versions of the Iowa Gambling Test. All patients were genotyped for serotonin transporter promoter polymorphism (5-HTTLPR) and received the Temperament and Character Inventory (TCI). RESULTS: Patients with the ll genotype achieved higher persistence scores and used more optimal decision-making strategy on the ABCD task compared with patients with the ss genotype. Higher persistence was associated with better performance on the ABCD task, and higher harm-avoidance was associated with worse performance on the EFGH task. LIMITATIONS: Healthy control volunteers were not included. Personality traits and decision-making were not assessed with multiple questionnaires and tasks. Type I errors cannot be excluded. CONCLUSIONS: Decision-making strategy is influenced by personality traits and genetic variations in patients with MDD. Patients carrying the ss variant of the 5-HTTLPR show less persistence and tend to be influenced by high immediate reward.

Alzheimer's lymphocytes are resistant to ultraviolet B-induced apoptosis.

In the present pilot investigation, the susceptibility of T-lymphocytes from Alzheimer's disease (AD) subjects (n=22) and aged-matched, non-demented controls (CNT) (n=12) was examined with ultraviolet (UV) B light-induced apoptosis in vitro. The basal apoptotic ratios were similar in both groups. However, the AD lymphocytes displayed significantly (p<0.0001) lower apoptotic levels than those of the CNT lymphocytes at all of the applied UVB exposure doses (100, 200 and 300 mJ/cm(2)). These observations indicate that AD lymphocytes are more resistant than CNT lymphocytes to UVB irradiation.

Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline.

Recovery from cardiac surgery is marred for many patients by the development of neurological, psychological or cognitive dysfunction. An uncontrolled inflammatory reaction, in response to surgical stress, may be responsible. To confirm this hypothesis, the present study evaluated changes in the levels of cytokines in cerebrospinal fluid after coronary artery bypass grafting. One week post-operatively, the concentration of the pro-inflammatory cytokine interleukin-6 markedly increased; 6 months after surgery, however, its level normalized with an increased concentration of the anti-inflammatory interleukin-4. This suggests that a regulated immune response may participate in developing adverse neurologic events and complications following cardiac interventions, and cytokines in the cerebrospinal fluid may serve as specific biomarkers and predictors of developing cognitive decline after coronary surgery.

Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis.

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

Alterations of seizure-induced c-fos immunolabelling and gene expression in the rat cerebral cortex following dexamethasone treatment.

We examined the effects of dexamethasone on the expression of the inducible transcription factor c-fos in 4-aminopyridine (4-AP) seizures. Induction of c-fos mRNA due to 4-AP-elicited convulsion was detected by means of the polymerase chain reaction (PCR) in samples from the neocortex. Adult male rats were pretreated with different doses of dexamethasone (0.5, 1, 3, 5mg/kg body weight); 1h later 5mg/kg 4-AP was injected intraperitoneally. Controls received the solvent of dexamethasone. Pretreatment with dexamethasone provided significant symptomatic protection against 4-AP-induced convulsions. Immunohistochemistry was used to evaluate the presence of the c-fos protein. The number of Fos-immunoreactive nuclei per section area was measured in the neocortex and hippocampus. Pretreatment with dexamethasone resulted in a dose-dependent, significant decrease of seizure-induced Fos-protein immunoreactivity in the neocortex, in the hilum of the dentate fascia, as well as in regions CA1-3 of the hippocampus, compared to control animals. Brains processed for mRNA isolation and PCR, displayed a significant increase of c-fos mRNA following the 4-AP treatment, while pretreatment with dexamethasone did not prevent or decrease this boosted c-fos mRNA expression. We conclude that seizure-induced c-fos expression and intracellular Fos-protein localization are mediated by transmitter and receptor systems, and dexamethasone significantly decreases Fos immunoreactivity, probably by regulating the intracellular traffic of the protein. We also conclude that dexamethasone does not interfere with the genomic regulation of c-fos mRNA synthesis.