Reviewing the Potential Therapeutic Approaches Targeting the Modulation of Gastrointestinal Microflora in Schizophrenia

Schizophrenia (SCZ) is a severe brain disorder characterized by an intriguing clinical panel that has begun to gain interest due to its particular phenotype. Having considered the role of gut microflora in psychiatry, the latest discoveries might offer further insight into the underlying mechanisms. Thus, we aimed to offer an updated overview of the therapeutic potential of microorganism-derived supplements alongside dedicated protocols that target the re-establishment of the host’s eubiosis. Based on combinations of specific keywords, we performed searches in four databases (PubMed/Medline, ISI Web of Knowledge, Scopus, and ScienceDirect) for the established interval (2018–2022) and identified twenty two eligible cases, restricted only to human patients’ experiences. Up until the writing of this manuscript, it has been revealed that the administration of specific lactic acid bacteria strains (Lactobacillus and Bifidobacterium), or those combined with vitamin D and selenium, maintain the integrity of the gut flora, preventing antagonistic effects including inflammation, antipsychotic-related body weight gain (olanzapine) and other metabolic dysfunctionalities. However, there are multiple antipsychotics that exert a potent effect upon gut flora, influencing a plethora of pathways and creating a dysbalance ratio between beneficial and opportunistic pathogens. Risperidone, amisulpride, and clozapine are just a few examples, but the current literature is unfortunately inconsistent and reported data is contradictory, which is why we support additional studies in this context. Moreover, we further argue the utility of studying how distinct controlled substances influence microbial communities, considering that ketamine is proved to alleviate depressive-like behavior as opposed to amphetamine and phencyclidine, which are known substances to trigger SCZ-like symptoms in experimental models. Probiotics may be regarded as the most consequential vehicle through which the gut flora can be successfully influenced, in adequate doses exerting a beneficial role as an alternative approach to alleviate SCZ symptoms

Oxidative Stress Implications in the Affective Disorders: Main Biomarkers, Animal Models Relevance, Genetic Perspectives, and Antioxidant Approaches

The correlation between the affective disorders and the almost ubiquitous pathological oxidative stress can be described in a multifactorial way, as an important mechanism of central nervous system impairment. Whether the obvious changes which occur in oxidative balance of the affective disorders are a part of the constitutive mechanism or a collateral effect yet remains as an interesting question. However it is now clear that oxidative stress is a component of these disorders, being characterized by different aspects in a disease-dependent manner. Still, there are a lot of controversies regarding the relevance of the oxidative stress status in most of the affective disorders and despite the fact that most of the studies are showing that the affective disorders development can be correlated to increased oxidative levels, there are various studies stating that oxidative stress is not linked with the mood changing tendencies. Thus, in this minireview we decided to describe the way in which oxidative stress is involved in the affective disorders development, by focusing on the main oxidative stress markers that could be used mechanistically and therapeutically in these deficiencies, the genetic perspectives, some antioxidant approaches, and the relevance of some animal models studies in this context

PRELIMINARY DATA ON SOME BEHAVIORAL CHANGES INDUCED BY SHORT-TERM INTRAPERITONEAL OXYTOCIN ADMINISTRATION IN AGED RATS

Introduction: Oxytocin (OT) is a well-known neuropeptides which together with vasopressin, melatonin, insulin and other hormones can alter both behavior and physiological or neuronal functions. This growing interest on OT roles is also based on the demonstrated beneficial effects as a stress reliever and a social bonding agent. The association between old age and OT was only vaguely studied. Little or few is known on the effect of the OT hormone on the old body. Hereby, we present our preliminary results in the research on behavioral changes regarding the intraperitoneal administration of OT in aged rats. Subjects and methods: OT was administered for 8 days in Wistar aged rats in parallel with saline administration for control group. Behavioral markers were assessed in some specific behavioral tasks, such as the Y-Maze test for short-term working memory, Open Field test, Elevated Plus Maze, and Forced Swim test for anxious and depressive behavior assessment, and Three-chambered Maze test for sociability assessment. Results: Increased mobility and decreased anxiety behaviors were reported for the aged intraperitoneal OT-treated animals, as compared with controls, during FST and OFT, and respectively FST, EPM, and OFT. Also, decreased depressive-like behaviors were observed in the same animal group during FST and ST. Moreover, a decrease in anxiolytic behavior was observed as exposed to stressful stimuli (such as grooming behavior in OFT, and forced grooming behavior in ST), and as exposed to social stimuli (such as grooming behavior in TCT). Similarly, significant differences were obtained regarding the social behavior of the intraperitoneal OT-treated animal as compared to control group, the animals showing increased sociability and social preference for the stranger animal in TCT. However, no significant effects on the working memory (assessed as spontaneous alternation in YMT) were observed. Conclusions: Intraperitoneal administration of OT in aged rats has clear effects on anxious and depressive behavior, but no significant effects on the working memory. Also, several beneficial effects of OT on social preferences and sociability were observed

Preliminary Data on the Interaction between Some Biometals and Oxidative Stress Status in Mild Cognitive Impairment and Alzheimer’s Disease Patients

Increased interest regarding the biometal mechanisms of action and the pathways in which they have regulatory roles was lately observed. Particularly, it was shown that biometal homeostasis dysregulation may lead to neurodegeneration including Alzheimer’s disease, Parkinson disease, or prion protein disease, since important molecular signaling mechanisms in brain functions implicate both oxidative stress and redox active biometals. Oxidative stress could be a result of a breakdown in metal-ion homeostasis which leads to abnormal metal protein chelation. In our previous work, we reported a strong correlation between Alzheimer’s disease and oxidative stress. Consequently, the aim of the present work was to evaluate some of the biometals’ levels (magnesium, manganese, and iron), the specific activity of some antioxidant enzymes (superoxide dismutase and glutathione peroxidase), and a common lipid peroxidation marker (malondialdehyde concentration), in mild cognitive impairment (n=15) and Alzheimer’s disease (n=15) patients, compared to age-matched healthy subjects (n=15). We found increased lipid peroxidation effects, low antioxidant defense, low magnesium and iron concentrations, and high manganese levels in mild cognitive impairment and Alzheimer’s disease patients, in a gradual manner. These data could be relevant for future association studies regarding the prediction of Alzheimer’s disease development risk or circling through stages by analyzing both active redox metals, oxidative stress markers, and the correlations in between

Cortisol and Oxytocin Could Predict Covert Aggression in Some Psychotic Patients

Background: The covert or indirect type of aggression has a risk of converting in violent acts and, considering that, it is very important to identify it in order to apply effective preventive measures. In cases of psychotic patients, the risk of becoming violent is harder to predict, as even neuter stimuli may be perceived as threat and trigger aggression. Treating all the psychiatric patients as potential aggressive subjects is not the best preventive measure as only a few of them are aggressive and this measure may further enhance the stigma on mentally ill patients. There is a current need for better understanding of covert aggression and to find objective measures, such as biological markers, that could be indicative of potential violent behavior. In this work, we try to investigate the role of cortisol and oxytocin as potential biomarkers of aggression in patients with psychosis. Material and Methods: We analyzed the level of peripheral oxytocin (pg/mL) and cortisol level (ng/mL) in 28 psychotic patients (they were not on psychotropic treatment at the moment of admission and those with substance abuse or personality disorder were excluded from the study) and correlated it with the intensity of aggression reported by the patient (overt and covert type) using the Overt Covert Aggression Inventory and the level of observed aggression of the patient in the past 7 days (rated by the health care provider) using the Modified Overt Aggression Scale. Results: We found that psychotic patients with a higher level of covert aggression had a lower level of cortisol (61.05 ± 8.04 ng/mL vs. 216.33 ± 12.6.9 ng/mL, p ˂ 0.01) and a higher level of oxytocin (102.87 ± 39.26 vs. 70.01 ± 25.07, p = 0.01) when compared with patients with a lower level of covert aggression. Furthermore, we observed significant negative correlation between cortisol and covert aggression (r = −0.676, p < 0.001) and between oxytocin and covert type of aggression (r = 0.382, p = 0.04). Moreover, we found that a lower level of cortisol together with a higher level of oxytocin are significant predictors of a style of internalized manifestation of aggression, with the predictive model explaining 55% of the variant of the internalized manifestation of aggression (F (2.25) = 17.6, p < 0.001, β = 0.35, R2 = 55.2). We did not find significant correlations between cortisol and overt aggression, and neither between oxytocin and overt aggression. Positive correlations were also found between the overt type of self-reported aggression and overt aggression reported by the rater (r = 0.459, p = 0.01). Conclusions: The importance of a predictive model in understanding covert aggression is imperative and the results of our study show that oxytocin and cortisol warrant to be further investigated in establishing a definitive predictive model for covert aggression

Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish (Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains

first_page settings Order Article Reprints Open AccessArticle Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish (Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains by Ovidiu-Dumitru Ilie 1,† [ORCID] , Raluca Duta 1, Ioana-Miruna Balmus 2,3, Alexandra Savuca 4 [ORCID] , Adriana Petrovici 5 [ORCID] , Ilinca-Bianca Nita 6, Lucian-Mihai Antoci 7, Roxana Jijie 8,† [ORCID] , Cosmin-Teodor Mihai 9 [ORCID] , Alin Ciobica 1,*, Mircea Nicoara 1,4 [ORCID] , Roxana Popescu 7,10 [ORCID] , Romeo Dobrin 11,* [ORCID] , Carmen Solcan 5,* [ORCID] , Anca Trifan 12,13 [ORCID] , Carol Stanciu 12,13 and Bogdan Doroftei 6 [ORCID] 1 Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania 2 Department of Exact and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University, Carol I Avenue, no 11, 700506 Iasi, Romania 3 Doctoral School of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue, 20A, 700506 Iasi, Romania 4 Doctoral School of Geosciences, Faculty of Geography-Geology, “Alexandru Ioan Cuza” University, Carol I Avenue, no 20A, 700505 Iasi, Romania 5 Department of Molecular Biology, Histology and Embryology, Faculty of Veterinary Medicine, University of Life Sciences “Ion Ionescu de la Brad”, Mihail Sadoveanu Street, no 3, 700490 Iasi, Romania 6 Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania 7 Department of Medical Genetics, University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania 8 Research Center on Advanced Materials and Technologies, Department of Exact and Natural Sciences, Institute of Inderdisciplinary Research, “Alexandru Ioan Cuza” University, Carol I Avenue, no 11, 700506 Iasi, Romania 9 Advanced Research and Development Center for Experimental Medicine (CEMEX), University of Medicine and Pharmacy “Grigore T. Popa”, University Street, no 16, 700115 Iasi, Romania 10 Department of Medical Genetics, “Saint Mary” Emergency Children’s Hospital, Vasile Lupu Street, no 62, 700309 Iasi, Romania add Show full affiliation list * Authors to whom correspondence should be addressed. † These authors equally contributed to this work. Antioxidants 2022, 11(10), 2040; https://doi.org/10.3390/antiox11102040 Received: 2 September 2022 / Revised: 3 October 2022 / Accepted: 13 October 2022 / Published: 17 October 2022 (This article belongs to the Special Issue Oxidative Stress and Neuroinflammation in Neurological and Neurodegenerative Disorders) Download Browse Figures Review Reports Versions Notes Abstract Parkinson’s disease (PD) is an enigmatic neurodegenerative disorder that is currently the subject of extensive research approaches aiming at deepening the understanding of its etiopathophysiology. Recent data suggest that distinct compounds used either as anticonvulsants or agents usually used as dopaminergic agonists or supplements consisting of live active lactic acid bacteria strains might alleviate and improve PD-related phenotypes. This is why we aimed to elucidate how the administration of rotenone (ROT) disrupts homeostasis and the possible neuroactive potential of valproic acid (VPA), antiparkinsonian agents (levodopa and carbidopa – LEV+CARB), and a mixture of six Lactobacillus and three Bifidobacterium species (PROBIO) might re-establish the optimal internal parameters. ROT causes significant changes in the central nervous system (CNS), notably reduced neurogenesis and angiogenesis, by triggering apoptosis, reflected by the increased expression of PARKIN and PINK1 gene(s), low brain dopamine (DA) levels, and as opposed to LRRK2 and SNCA compared with healthy zebrafish. VPA, LEV/CARB, and PROBIO sustain neurogenesis and angiogenesis, manifesting a neuroprotective role in diminishing the effect of ROT in zebrafish. Interestingly, none of the tested compounds influenced oxidative stress (OS), as reflected by the level of malondialdehyde (MDA) level and superoxide dismutase (SOD) enzymatic activity revealed in non-ROT-exposed zebrafish. Overall, the selected concentrations were enough to trigger particular behavioral patterns as reflected by our parameters of interest (swimming distance (mm), velocity (mm/s), and freezing episodes (s)), but sequential testing is mandatory to decipher whether they exert an inhibitory role following ROT exposure. In this way, we further offer data into how ROT may trigger a PD-related phenotype and the possible beneficial role of VPA, LEV+CARB, and PROBIO in re-establishing homeostasis in Danio rerio

Anisotropic flow of charged hadrons, pions and (anti-)protons measured at high transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}=2.76 TeV

The elliptic, $v_2$, triangular, $v_3$, and quadrangular, $v_4$, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions and (anti-)protons in Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range $|\eta|<0.8$ at different collision centralities and as a function of transverse momentum, $p_{\rm T}$, out to $p_{\rm T}=20$ GeV/$c$. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for $p_{\rm T}>8$ GeV/$c$. The small $p_{\rm T}$ dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to $p_{\rm T}=8$ GeV/$c$. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least $p_{\rm T}=8$ GeV/$c$ indicating that the particle type dependence persists out to high $p_{\rm T}$.Comment: 16 pages, 5 captioned figures, authors from page 11, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/186

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286