Abstract Objective Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine ...dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha ( PPARα ) in schizophrenia, together with nicotine dependency, to investigate whether the PPARα -L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARα -L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARα -L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARα gene and nicotine dependency. Patients and methods Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction. Results A significant excess of PPARα -L162V genotypes and PPARα -162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs . 2.0%, and 9.1% vs . 1.0%, p < 0.01, respectively). We also revealed a significant PPARα genotype-smoking interaction that predicted positive symptom severity among male patients ( F = 4.43, p < 0.05). These data indicated that the PPARα -L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARα -L162V polymorphism and smoking for the time of onset of schizophrenia was detected ( p > 0.05, respectively). Conclusion We demonstrated two significant, yet weak effects. The first showed an effect of the PPARα -L162V polymorphism on the risk of nicotine dependency. The second linked the PPARα genotype-smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.
Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of ...γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aβ proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-βCTF-APP substrate and its different Aβ products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-βCTF-APP substrate and β-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-βCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and β-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aβ metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism.
Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We ...describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism.
Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation.
Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism.
We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction ...with its C99 substrate to the final release of toxic Aβ peptides.
The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles.
Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis.
Cilj: Istražili smo povezanost pojave pretilosti s kliničkim značajkama shizofrenije, poput dobi, trajanja bolesti, dobi nastupa bolesti, ovisnosti o pušenju i težine simptoma ocjenske ljestvice ...PANSS-a (engl. Positive and Negative Syndrome Scale – PANSS). Također smo testirali doprinos pretilosti biokemijskim parametrima: koncentracijama ukupnog kolesterola, LDL kolesterola (engl. low density lipoprotein cholesterol), HDL kolesterola (engl. high density lipoprotein cholesterol), triglicerida i glukoze u plazmi. Ispitanici i metode: U istraživanju su sudjelovala 142 kronična pacijenta sa shizofrenijom. Pretilim pacijentima smatrani su oni s vrijednostima indeksa tjelesne mase (ITM) > 30, dok su pacijenti s normalnom tjelesnom masom (ITM: 20 – 25) i pacijenti s prekomjernom tjelesnom masom (ITM: 25 – 30) klasificirani u nepretile. Rezultati: Nije uočena statistički značajna povezanost pretilosti s kliničkim značajkama (P > 0,05). Koncentracije ukupnog kolesterola i LDL kolesterola bile su značajno više u pretilih pacijentica u odnosu na nepretile pacijentice, dok su značajno više vrijednosti triglicerida uočene kod pretilih u odnosu na nepretile ispitanike oba spola (P < 0,05). Ipak, samo se trajanje bolesti pokazalo značajnim prediktorom vrijednosti triglicerida u pacijentica, dok je učinak pretilosti ostao izvan statističke značajnosti (P > 0.05). Pojava pretilosti opisuje približno 8,3 % varijabilnosti koncentracija triglicerida u muškaraca te 9,6 % i 13,8 % varijabilnosti koncentracija ukupnog kolesterola i LDL kolesterola u žena. Zaključak: Pretilost pridonosi isključivo biokemijskim parametrima u pacijenata sa shizofrenijom. U muškaraca determinira vrijednosti triglicerida, a u žena koncentracije ukupnog kolesterola i LDL kolesterola te opisuje približno 8,3 – 13,8 % varijabilnosti njihove koncentracije.
Aim: We investigated the association between obesity and clinical characteristics of schizophrenia, such as age, illness duration, age of illness onset, nicotine dependence and clinical psychopathology measured via Positive and Negative Syndrome Scale scores. We also tested whether obesity contributes to biochemical parameters: plasma total cholesterol, LDL cholesterol (low density lipoprotein cholesterol), HDL cholesterol (high density lipoprotein cholesterol), and triglyceride and glucose levels. Patients and methods: Our study group consisted of 142 chronically ill patients with schizophrenia. Patients were classified as obese with body mass index (BMI) values > 30, and non-obese, those who were overweight (BMI: 25 – 30), or those having a normal body weight (BMI: < 25). Results: We did not find statistically significant associations between obesity and clinical characteristics (P > 0.05). Plasma total cholesterol and LDL concentrations were significantly higher in obese females compared to non-obese females, and significantly greater plasma triglyceride values were observed among obese patients of both genders compared to non-obese (P < 0.05). However, only the illness duration significantly predicted triglyceride concentration in females, whereas the influence of obesity on triglyceride levels did not reach significance (P > 0.05). The obesity accounts for approximately 8.3 % variability of triglyceride values in males and 9.6 % and 13.8 % of total cholesterol and LDL cholesterol variability in females. Conclusion: The obesity significantly contributes only to biochemical parameters in patients with schizophrenia. In males, it determines triglyceride values, whereas in females, it underlies total cholesterol and LDL cholesterol levels, accounting for approximately 8.3 – 13.8 % of their variability.
Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of Aβ peptides and decrease in maximal activity of a membrane-embedded protease γ-secretase.
We ...compared activity of WT γ-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in Aβ-part of its APP substrate (Familial Alzheimer's disease). All 11 FAD mutations show linear correlation between the decrease in maximal activity and the clinically observed age-of-onset and age-of-death. Biphasic-inhibitors showed that a higher ratio between physiological Aβ-production and the maximal activity of γ-secretase can be observed in cells that can facilitate pathogenic changes in Aβ-products. For example, Aβ production in cells with WT γ-secretase is at 11% of its maximal activity, with delta-exon-9 mutant at 26%, while with M139V mutant is at 28% of the maximal activity. In the same conditions, G384A mutant is fully saturated and at its maximal activity. Similarly, Aβ production in cells with γ-secretase complex carrying Aph1AL component is 12% of its maximal activity, while in cells with Aph1B complex is 26% of its maximal activity. Similar to the cell-based studies, clinical studies of biphasic dose–response in plasma samples of 54 healthy individuals showed variable ratios between physiological Aβ production and the maximal activity of γ-secretase.
The increase in the ratio between physiological Aβ production and maximal activity of γ-secretase can be an early sign of pathogenic processes in enzyme-based, cell-based, and clinical studies of sporadic and Familiar Alzheimer's disease.
•We do not know how changes in γ-secretase activity can support pathogenesis in Alzheimer's disease.•Confusingly both increase and decrease in γ-secretase's activity can be observed in pathogenesis.•The decrease in γ-secretase capacity to process its substrate is a good indicator of pathogenic events.•Measurements of γ-secretase capacity to process its substrate can be used as an early diagnostic tool.•Measurements of γ-secretase capacity to process its substrate can be used in the development of drugs.
Cilj: Ispitali smo utječu li, i u kojoj mjeri, koncentracije lipida i glukoze u plazmi te vrijednosti indeksa tjelesne mase (engl. body mass index; BMI), na težinu kliničke slike shizofrenije u ...hrvatskih bolesnika, ovisno o njihovom pušačkom statusu.
Ispitanici i metode: U istraživanju je sudjelovalo 263 kroničnih bolesnika (muškarci/žene: 139/124). Težina kliničke slike procijenjena je korištenjem ocjenske ljestvice PANSS-a (engl. Positive and Negative Syndrome Scale) u akutnoj fazi bolesti tijekom posljednje hospitalizacije. U pušače su klasificirani ispitanici koji puše najmanje jednu cigaretu dnevno u periodu duljem od godine dana, a u nepušače oni koji su popušili manje od 100 cigareta tijekom života.
Rezultati: Koncentracije triglicerida, glukoze i vrijednosti BMI-a nisu pokazale povezanost s PANSS psihopatologijom, niti u bolesnika, niti u bolesnica, ovisno o pušačkom statusu (svi P > 0,05), a na težinu kliničke slike u bolesnica, utjecale su isključivo koncentracije kolesterola. Bolesnice pušači s višim koncentracijama LDL kolesterola (engl. low density lipoprotein cholesterol) imale su značajno niže vrijednosti općih i ukupnih simptoma (P = 0,023 i P = 0,015), dok su u bolesnica nepušača s višim koncentracijama HDL kolesterola (engl. high density lipoprotein cholesterol), uočene značajno niže vrijednosti pozitivnih i ukupnih PANSS simptoma (P = 0,041 i P = 0,002). Koncentracija LDL kolesterola opisuje približno 20% varijabilnosti općih simptoma i 23% varijabilnosti ukupnih simptoma u bolesnica pušača, a vrijednosti HDL kolesterola pridonose s otprilike 39% težini pozitivnih simptoma te s 69% težini ukupnih simptoma u bolesnica nepušača.
Zaključak: Na temelju naših rezultata možemo zaključiti da na težinu kliničke slike shizofrenije utječu isključivo koncentracije kolesterola u bolesnica. Nadalje, koncentracije kolesterola opisuju mali do umjereno veliki udio varijabilnosti PANSS psihopatologije.
Cilj: Shizofreniju karakterizira visoka učestalost ovisnosti o pušenju, kao i visoka učestalost metaboličkog sindroma. Unatoč tome, malo se zna o učinku pušenja na komponente metaboličkog sindroma u ...toj bolesti. Cilj ovog rada bio je ispitati doprinosi li, i u kojoj mjeri, pojava ovisnosti o pušenju, koncentracijama lipida i glukoze u plazmi, te vrijednostima indeksa tjelesne mase (BMI), u skupini hrvatskih bolesnika sa shizofrenijom.
Ispitanici i metode: U istraživanju je sudjelovalo 263 kroničnih bolesnika (muškarci/žene: 139/124) s dijagnozom shizofrenije utvrđenom prema DSM-IV klasifikaciji (engl. Diagnostic and statistical manual for mental disorders – DSM-IV). U pušače su klasificirani ispitanici koji puše najmanje jednu cigaretu dnevno u periodu duljem od godine dana, a u nepušače oni koji su popušili manje od 100 cigareta tijekom života.
Rezultati: Unatoč visokoj stopi ovisnosti o pušenju (muškarci: 70,5%; žene: 60,5%), nije pronađena značajna razlika u koncentracijama lipida i glukoze u plazmi te vrijednostima BMI-a između muškaraca pušača i nepušača, a u žena su se samo koncentracije triglicerida razlikovale ovisno o pušačkom statusu. Pri tome su bolesnice koje puše imale nešto više vrijednosti triglicerida u usporedbi s bolesnicama nepušačima (1,6 ± 0,7 vs. 1,3 ± 0,5; F = 4,25, P = 0,042). Ipak, multipla regresijska analiza pokazala je da je samo dob značajni prediktor vrijednosti triglicerida u bolesnica (β = 0,41; promjena R2 = 0,171; P < 0,001), dok je učinak pušenja na koncentracije triglicerida, kao i na ostale ispitane metaboličke parametre, u bolesnika i bolesnica, ostao izvan granica statističke značajnosti (P > 0,05).
Zaključak: Na temelju naših rezultata, možemo zaključiti da pušenje ne utječe na koncentracije lipida i glukoze u plazmi te vrijednosti BMI-a niti u bolesnika, niti u bolesnica sa shizofrenijom.
In terms of health and healthcare cyberspace and virtual reality can be used differently and for different purposes and consequently create different outcomes. The three main areas which we shall ...discuss here are: 1) cyberspace as provider of health information and self-help resources, since the anonymity cyberspace provides is particularly important in the highly stigmatized field of psychiatry where a large number of people never seek professional help, which in turn negatively affects not only the person in question, but the family and ultimately the society (work efficiency, disability-adjusted life year - DALY, etc.), 2) cyberspace and virtual reality (VR) as cause of psychopathology, starting from violent behaviour, to addictive behaviour and other, 3) and finally cyberspace and VR as providers of efficient professional therapy in the field of psychiatry.
•This is the first investigation of the association between the skin flush response to niacin and lipid and glucose metabolism in schizophrenia.•Skin flush response to niacin was not significantly ...associated with plasma cholesterol or glucose levels.•Niacin-induced skin flushing was positively and strongly associated with plasma triglyceride levels.
The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.
PDF
