Band 15, Heft 1

Objective Heterozygous mutations within the voltage-gated sodium channel α subunit ( SCN1A ) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results The SCN1A related antisense RNAs SCN1A -dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A -usAS (upstream AS, SCN1A -AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A -usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A -dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A -dsAS transcripts. Conclusion These findings support the role of SCN1A -dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A -dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

Background Silibinin has been found to inhibit glioblastoma (GBM) progression. However, the underlying molecular mechanism by which Silibinin regulates GBM process remains unclear. Methods GBM cell proliferation, apoptosis, invasion, and stemness are assessed by cell counting kit-8 assay, EdU assay, flow cytometry, transwell assay, and sphere formation assay. Western blot is used to measure the protein expression levels of apoptosis-related markers, solute carrier family 1 member 5 (SLC1A5), and Yin Yang-1 (YY1). Glutamine consumption, glutamate production, and α-ketoglutarate production are detected to evaluate glutamine metabolism in cells. Also, SLC1A5 and YY1 mRNA levels are examined using quantitative real-time PCR. Chromatin immunoprecipitation assay and dual-luciferase reporter assay are used to detect the interaction between YY1 and SLC1A5. Mice xenograft models are constructed to explore Silibinin roles in vivo . Results Silibinin inhibits GBM cell proliferation, invasion, stemness, and glutamine metabolism, while promotes apoptosis. SLC1A5 is upregulated in GBM and its expression is decreased by Silibinin. SLC1A5 overexpression abolishes the anti-tumor effect of Silibinin in GBM cells. Transcription factor YY1 binds to SLC1A5 promoter region to induce SLC1A5 expression, and the inhibition effect of YY1 knockdown on GBM cell growth, invasion, stemness, and glutamine metabolism can be reversed by SLC1A5 overexpression. In addition, Silibinin reduces GBM tumor growth by regulating YY1/SLC1A5 pathway. Conclusion Silibinin plays an anti-tumor role in GBM process, which may be achieved via inhibiting YY1/SLC1A5 pathway.

Our previous studies have shown that early exercise intervention after stroke increases neural activity and synaptic plasticity and promotes the recovery of nerve fiber bundle integrity in the brain. However, the effect of exercise on the repair of myelin in the brain and the related mechanism are still unclear. In this study, we randomly divided the rats into three groups. Before and after 28 days of intervention, body weight, nerve function, the infarct size, white matter fiber bundle integrity, and nerve myelin structure and function were observed by measuring body weight, analysis of modified neurological severity score, CatWalk gait analysis, MRI, luxol fast blue staining, immunofluorescence, and transmission electron microscopy. Changes in the expression of proteins in the MEK/ERK pathway were assessed. The results showed that early exercise intervention resulted in neurological recovery, decreased the infarct volume and increased nerve fiber integrity, the myelin coverage area, myelin basic protein (MBP) fluorescence intensity expression, and myelin thickness. Furthermore, the expression level of MBP was significantly increased after early exercise intervention, while the expression levels of p-MEK1/2 and p-ERK1/2 were significantly reduced. In the cell study, MBP expression levels were significantly higher in the oxygen and glucose deprivation and administration group.In summary, early exercise intervention after stroke can promote myelin repair by inhibiting the MEK/ERK signaling pathway.

Background Both the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) and the Corticosteroid randomization after significant head injury (CRASH) models are globally acknowledged prognostic algorithms for assessing traumatic brain injury (TBI) outcomes. The aim of this study is to externalize the validation process and juxtapose the prognostic accuracy of the CRASH and IMPACT models in moderate-to-severe TBI patients in the Chinese population. Methods We conducted a retrospective study encompassing a cohort of 340 adult TBI patients (aged > 18 years), presenting with Glasgow Coma Scale (GCS) scores ranging from 3 to 12. The data were accrued over 2 years (2020–2022). The primary endpoints were 14-day mortality rates and 6-month Glasgow Outcome Scale (GOS) scores. Analytical metrics, including the area under the receiver operating characteristic curve for discrimination and the Brier score for predictive precision were employed to quantitatively evaluate the model performance. Results Mortality rates at the 14-day and 6-month intervals, as well as the 6-month unfavorable GOS outcomes, were established to be 22.06, 40.29, and 65.59%, respectively. The IMPACT models had area under the curves (AUCs) of 0.873, 0.912, and 0.927 for the 6-month unfavorable GOS outcomes, with respective Brier scores of 0.14, 0.12, and 0.11. On the other hand, the AUCs associated with the six-month mortality were 0.883, 0.909, and 0.912, and the corresponding Brier scores were 0.15, 0.14, and 0.13, respectively. The CRASH models exhibited AUCs of 0.862 and 0.878 for the 6-month adverse outcomes, with uniform Brier scores of 0.18. The 14-day mortality rates had AUCs of 0.867 and 0.87, and corresponding Brier scores of 0.21 and 0.22, respectively. Conclusion Both the CRASH and IMPACT algorithms offer reliable prognostic estimations for patients suffering from craniocerebral injuries. However, compared to the CRASH model, the IMPACT model has superior predictive accuracy, albeit at the cost of increased computational intricacy.

Background Forkhead box P3 ( FOXP3 ) plays a critical role in the pathogenesis of autoimmune disorders. In the present study, we genotyped three single-nucleotide polymorphisms, namely, rs2232365, rs3761548, and rs3761549, to determine the relationship between FOXP3 polymorphisms and neuromyelitis optica spectrum disorder (NMOSD) susceptibility among the Northern Chinese Han population. Materials and methods We genotyped single nucleotide polymorphisms at loci of the FOXP3 gene (rs2232365, rs3761548, and rs3761549136) in 136 NMOSD patients and 224 healthy subjects using the multiplex SNaPshot technique. Allele, genotype, and haplotype frequencies were compared. qPCR was used to analyze the mRNA expression levels of FOXP3 in the peripheral blood mononuclear cells of 63 NMOSD patients and 35 healthy subjects. Non-parametric tests were used to test the FOXP3 mRNA expression across the different groups. Results The minor allele frequency (MAF) of G in rs2232365 was markedly lower in the NMOSD group than in the control group (odds ratio [OR] = 0.57, 95% confidence interval [95% CI]: 0.41–0.79, p = 0.001). Using genetic (codominant, dominant, and recessive) models and performing haplotype analyses, the MAF of G in rs2232365 was shown to be associated with protection against NMOSD in this population. Furthermore, haplotype analysis revealed that the haplotype GCT and the rs2232365, rs3761548, and rs3761549 alleles predicted protection against NMOSD (OR = 0.63, 95% CI = 0.41–0.97, p = 0.038). The proportions of the three genotypes of rs2232365 ( p = 0.001) were not significantly different between the moderate-to-severe (Expanded Disability Status Scale (EDSS) ≥ 3 points) and mild (EDSS < 3 points) groups. Evidently, the proportion of patients with the AA genotype (64.3%) among the rs2232365 patients was significantly greater in the moderate-to-severe group than in the mild group (36.4%). However, the proportion of patients with the GG genotype (15.2%) among the rs2232365 patients was significantly greater in the mild group than in the moderate-to-severe group (2.9%). The mRNA expression of FOXP3 was markedly greater in the NMOSD group than in the control group ( p = 0.001). Nevertheless, acute non-treatment patients exhibited lower FOXP3 mRNA expression than healthy controls and patients in the remission group ( p = 0.004 and 0.007, respectively). Conclusion FOXP3 polymorphisms and haplotypes are related to NMOSD susceptibility among the Han Chinese population. The minor allele G of FOXP3 rs2232365 and the haplotype GCT are associated with protection against NMOSD. The GG genotype may decrease the severity of NMOSD, whereas the AA genotype is related to moderate-to-severe NMOSD. FOXP3 mRNA expression is greater in patients with NMOSD than in healthy controls. However, it is decreased in acute non-treatment patients compared with healthy controls.

Background The deposition of Aβ 42 has been regarded as one of the important pathological features of Alzheimer’s disease (AD). However, drug development for Aβ 42 toxicity has been progressed slowly. Objective Our aim was to introduce the effect and related mechanism of trehalose on an Aβ arc (arctic mutant Aβ 42 ) Drosophila AD model. Methods The human Aβ arc was expressed in Drosophila to construct the AD model. Trehalose was added to the culture vial. The movement ability was determined by detecting climbing ability and flight ability. Enzyme-linked immunosorbent assay was used to detect the levels of Aβ arc , ATP, and lactate. Electron microscopy assay, mitochondrial membrane potential assay, and mitochondrial respiration assay were used to assess the mitochondrial structure and function. Results Trehalose strongly improved the movement ability of Aβ arc Drosophila in a concentration gradient-dependent manner. Furthermore, trehalose increased the content of ATP and decreased the content of Aβ arc and lactate both in the brain and thorax of Aβ arc Drosophila . More importantly, the mitochondrial structure and function were greatly improved by trehalose treatment in Aβ arc Drosophila . Conclusion Trehalose improves movement ability at least partly by reducing the Aβ arc level and restoring the mitochondrial structure and function in Aβ arc Drosophila .

Background Death among resuscitated patients is mainly caused by brain injury after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The angiotensin converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor (MasR) axis has beneficial effects on brain injury. Therefore, we examined the roles of the ACE2/Ang-(1-7)/MasR axis in brain injury after CA/CPR. Method We used a total of 76 male New Zealand rabbits, among which 10 rabbits underwent sham operation and 66 rabbits received CA/CPR. Neurological functions were determined by assessing serum levels of neuron-specific enolase and S100 calcium-binding protein B and neurological deficit scores. Brain water content was estimated. Neuronal apoptosis in the hippocampus was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assays. The expression levels of various genes were measured by enzyme-linked immunosorbent assay and western blotting. Results Ang-(1-7) (MasR activator) alleviated CA/CPR-induced neurological deficits, brain edema, and neuronal damage, and A779 (MasR antagonist) had the opposite functions. The stimulation of ACE2/Ang-(1-7)/MasR inactivated the ACE/Ang II/AT1R axis and activated PI3K/Akt signaling. Inhibiting PI3K/Akt signaling inhibited Ang-(1-7)-mediated protection against brain damage after CA/CPR. Conclusion Collectively, the ACE2/Ang-(1-7)/MasR axis alleviates CA/CPR-induced brain injury through attenuating hippocampal neuronal apoptosis by activating PI3K/Akt signaling.

The ventral bed nucleus of the stria terminalis (vBNST) plays a key role in cocaine addiction, especially relapse. However, the direct effects of cocaine on corticotropin-releasing hormone (CRH) neurons in the vBNST remain unclear. Here, we identify that cocaine exposure can remarkably attenuate the intrinsic excitability of CRH neurons in the vBNST in vitro . Accumulating studies reveal the crucial role of Sigma-1 receptors (Sig-1Rs) in modulating cocaine addiction. However, to the authors’ best knowledge no investigations have explored the role of Sig-1Rs in the vBNST, let alone CRH neurons. Given that cocaine acts as a type of Sig-1Rs agonist, and the dramatic role of Sig-1Rs played in intrinsic excitability of neurons as well as cocaine addiction, we employ BD1063 a canonical Sig-1Rs antagonist to block the effects of cocaine, and significantly recover the excitability of CRH neurons. Together, we suggest that cocaine exposure leads to the firing rate depression of CRH neurons in the vBNST via binding to Sig-1Rs.

Background Freezing of gait (FOG) in Parkinson’s disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine “OFF” state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear. Objective To evaluate how dopamine therapy alters resting state functional connectivity (rsFC) of the fronto-striato-limbic circuitry in PD freezers, and whether the degree of connectivity change is related to freezing severity and anxiety. Methods Twenty-three PD FOG patients underwent MRI at rest (rsfMRI) in their clinically defined “OFF” and “ON” dopaminergic medication states. A seed-to-seed based analysis was performed between a priori defined limbic circuitry ROIs. Functional connectivity was compared between OFF and ON states. A secondary correlation analyses evaluated the relationship between Hospital Anxiety and Depression Scale (HADS)-Anxiety) and FOG Questionnaire with changes in rsFC from OFF to ON. Results PD freezers’ OFF compared to ON showed increased functional coupling between the right hippocampus and right caudate nucleus, and between the left putamen and left posterior parietal cortex (PPC). A negative association was found between HADS-Anxiety and the rsFC change from OFF to ON between the left amygdala and left prefrontal cortex, and left putamen and left PPC. Conclusion These findings suggest that dopaminergic medication partially modulates the frontoparietal-limbic-striatal circuitry in PD freezers, and that the influence of medication on the amygdala, may be related to clinical anxiety in freezer.

Objectives The FT4-to-FT3 ratio (FFR) variations in patients with subacute combined spinal cord degeneration (SCSD) as a potentially useful prognostic indicator are still unknown. This study aimed to investigate the changes of FFR as a potentially valuable prognostic predictor in patients with SCSD. Methods This study included 144 consecutive SCSD patients who received standard diagnostic and therapeutic procedures between January 2015 and December 2021 and were admitted to the Department of Neurology at the First Affiliated Hospital of Bengbu Medical University. At the time of admission, we gathered data on all patients’ demographics, daily routines, previous chronic conditions, medication histories, and other clinical details. For the purpose of measuring FFR, blood samples were specifically taken within 48 h of admission. The degree of neurological impairment of patients was assessed using the functional disability scale at the time of admission. At 6 months following discharge, the Modified Rankin Scale (mRS) was used to evaluate the clinical prognosis. To evaluate the relationship between the FFR and the risks of a poor outcome (mRS > 2), univariate and multivariate logistic regression analysis was utilized. The significance of the FT4/FT3 ratio in predicting the clinical outcomes in SCSD patients 6 months after discharge was assessed using the area under curve-receiver operating characteristic (AUC-ROC). Results About 90 patients (62.5%) of the 144 patients had poor outcomes, while 54 (37.5%) had favorable outcomes. Higher FFR at admission was independently linked to higher odds of a poor outcome, according to a logistic analysis. With an optimized cutoff value of >2.843, the FFR exhibited the maximum accuracy for predicting a poor outcome, according to the AUC‒ROC curve (AUC 0.731, P < 0.001; sensitivity, 77.8%; specificity, 83.3%). FFR was identified as an independent predictor of poor outcomes by multivariate logistic regression (OR, 2.244; 95% CI, 1.74–2.90; P < 0.001). Conclusions We discovered that in patients who had a bad result 6 months after discharge, the FFR had dramatically increased at the time of admission, providing a unique prognostic marker in patients with SCSD.

Calmodulin-dependent protein kinases (CaMKs) are widely regarded as “memory molecules” due to their role in controlling numerous neuronal functions in the brain, and the CaMK signaling pathway plays a crucial role in controlling synaptic plasticity. Suanzaoren decoction (SZRD) can improve depression-like behavior and thus has potential benefits in the clinical treatment of depression; however, its mechanism of action is not fully understood. In this study, we found that key proteins in the CaMK signaling pathway were regulated by the decoction used to treat depression. The purpose of this research was to ascertain if the SZRD’s therapeutic efficacy in the treatment of depression is associated with the modulation of key proteins in the CaMK signaling pathway. A rat model of depression was created by exposing the animals to chronic, unexpected, mild stress. Model rats were given intragastric administration of SZRD or fluoxetine every morning once a day. Protein and mRNA relative expression levels of CaM, CaMK I, and CaMK IV in the hippocampus were measured by Western blot, quantitative polymerase chain reaction, and immunohistochemistry in the hippocampus. Our findings demonstrated that SZRD significantly improved the mood of depressed rats. This indicates that SZRD, by modulating the CaMK signaling system, may alleviate depressive symptoms and lessen work and life-related pressures.

Cerebral edema (CE) and hemorrhagic transformation (HT) are frequent and unpredictable events in patients with acute ischemic stroke (AIS), even when an effective vessel recanalization has been achieved. These complications, related to blood-brain barrier (BBB) disruption, remain difficult to prevent or treat and may offset the beneficial effect of recanalization, and lead to poor outcomes. The aim of this translational study is to evaluate the association of circulating and imaging biomarkers with subsequent CE and HT in stroke patients with the dual purpose of investigating possible predictors as well as molecular dynamics underpinning those events and functional outcomes. Concurrently, the preclinical study will develop a new mouse model of middle cerebral artery (MCA) occlusion and recanalization to explore BBB alterations and their potentially harmful effects on tissue. The clinical section of the study is based on a single-center observational design enrolling consecutive patients with AIS in the anterior circulation territory, treated with recanalization therapies from October 1, 2015 to May 31, 2020. The study will employ an innovative evaluation of routine CT scans: in fact, we will assess and quantify the presence of CE and HT after stroke in CT scans at 24 h, through the quantification of anatomical distortion (AD), a measure of CE and HT. We will investigate the relationship of AD and several blood biomarkers of inflammation and extracellular matrix, with functional outcomes at 3 months. In parallel, we will employ a newly developed mouse model of stroke and recanalization, to investigate the emergence of BBB changes 24 h after the stroke onset. The close interaction between clinical and preclinical research can enhance our understanding of findings from each branch of research, enabling a deeper interpretation of the underlying mechanisms of reperfusion injury following recanalization treatment for AIS.

Thyroid hormones (THs) are essential in neuronal and glial cell development and differentiation, synaptogenesis, and myelin sheath formation. In addition to nuclear receptors, TH acts through αvβ3-integrin on the plasma membrane, influencing transcriptional regulation of signaling proteins that, in turn, affect adhesion and survival of nerve cells in various neurologic disorders. TH exhibits protective properties during brain hypoxia; however, precise intracellular mechanisms responsible for the preventive effects of TH remain unclear. In this study, we investigated the impact of TH on integrin αvβ3-dependent downstream systems in normoxic and hypoxic conditions of pheochromocytoma PC12 cells. Our findings reveal that triiodothyronine (T3), acting through αvβ3-integrin, induces activation of the JAK2/STAT5 pathway and suppression of the SHP2 in hypoxic PC12 cells. This activation correlates with the downregulation of the expression palmitoyltransferase-ZDHHC2 and ZDHHC9 genes, leading to a subsequent decrease in palmitoylation and phosphorylation of Fyn tyrosine kinase. We propose that these changes may occur due to STAT5-dependent epigenetic silencing of the palmitoyltransferase gene, which in turn reduces palmitoylation/phosphorylation of Fyn with a subsequent increase in the survival of cells. In summary, our study provides the first evidence demonstrating the involvement of integrin-dependent JAK/STAT pathway, SHP2 suppression, and altered post-translational modification of Fyn in protective effects of T3 during hypoxia.

Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ’s pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ’s α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4 + CD25 + Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4 + CD25 + Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes ( P ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons’ apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ’s structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.

Introduction Cortical lesions can cause major sensory and motor impairments, representing a significant challenge in neuroscience and clinical medicine. Limbal mesenchymal stem cells (LMSCs), renowned for their remarkable ability to proliferate and distinct characteristics within the corneal epithelium, offer a promising opportunity for regenerative treatments. This study aimed to assess whether the transplantation of LMSCs could improve tactile ability in rats with lesions of the barrel cortex. Methods In this experimental study, we divided 21 rats into three groups: a control group, a lesion group with cortical cold lesion induction but no stem cell treatment, and a group receiving LMSC transplantation following cold lesion induction. We conducted 3-week sensory assessments using a texture discrimination test and an open-field test. We also performed Nissl staining to assess changes on the cellular level. Results Rats in the LMSC transplantation group demonstrated significant improvements in their ability to discrimination textures during the second and third weeks compared to those in the lesion group. The open-field test results showed an increased exploratory behavior of rats in the LMSC transplantation group by the third week compared to the lesion group. Additionally, Nissl staining revealed cellular alterations in the damaged cortex, with a significant distinction observed between rats in the LMSCs and lesion group. Conclusion The findings suggest that LMSC transplantation enhances sensory recovery in rats with cortical lesions, particularly their ability to discriminate textures. LMSC transplantation benefits brain tissue reparation after a cold lesion on the somatosensory cortex.

This study aimed to elucidate the impact of the TTBK2 T3290C mutation (MUT) associated with Spinocerebellar Ataxia 11 (SCA11) on TTBK2 expression, function, and ciliogenesis. Lymphocytes were isolated from peripheral blood samples of SCA11 family members with the MUT and healthy controls (wild-type, WT). HEK-293 cells transfected with either WT or MUT TTBK2 plasmids were used to assess the MUT’s impact on TTBK2 protein expression, enzymatic activity, and its binding to Cep164 protein. Mouse embryonic fibroblast cells transfected with WT or MUT TTBK2 plasmids examined the MUT’s effect on cilia formation. Clinically, there was no significant difference in the expression of TTBK2 between the SCA11 patients and healthy individuals. The TTBK2 T3290C MUT did not affect protein expression or enzymatic activity but did reduce ciliary formation in embryonic cells and decreased binding affinity to Cep164. Therefore, our data suggested that the TTBK2 T3290C MUT in SCA11 may impair ciliogenesis by weakening the interaction with Cep164.

Objective Rodent models may help investigations on the possible link between autism spectrum disorder and increased permeability of the gastrointestinal (GI) tract since autistic patients frequently manifested GI troubles as comorbidities. Methods Forty young male western Albino rats, weighing approximately 60–70 g and aged 3–4 weeks, were used. In each of the six experimental groups, eight animals were treated as follows. The mice in the control group (I) received phosphate-buffered saline orally. For 3 days, the animals in the propionic acid (PPA)-treated groups (II and III) were given an oral neurotoxic dose of PPA (250 mg/kg body weight each day). Group II was euthanized after 3 days; however, Group III was left alive to be euthanized alongside the other groups. The animals were kept at 22 ± 1°C and allowed to access water and normal food as needed. Identical dosages of PPA were given to the rats in the three treatment groups (IV, V, and VI), and for 3 weeks, they were given the following treatments: 0.2 g/kg body weight of pure Bifidobacterium infantis , a probiotic mixture of PROTEXIN®, Somerset, UK and pure Lactobacillus bulgaricus , respectively. The six groups underwent measurements of serum zonulin and occludin as variables associated with leaky gut, glutathione, malondialdehyde, and catalase as oxidative stress-related variables, with gamma-aminobutyric acid (GABA) receptor gene expression. Results This study demonstrated the potential effects of pure or mixed probiotics in lowering zonulin and occludin as markers of increased intestinal permeability, enhancing GABA receptor expression, and reducing oxidative stress as neurotoxic effects of PPA. Conclusions This study demonstrates that various probiotics protect gut barrier function and could be used to alleviate increased intestinal permeability caused by oxidative stress and impaired GABA signaling as a result of PPA neurotoxicity, addressing the clinical implications of probiotic supplements.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. A key challenge associated with this condition is achieving an early diagnosis. The current study seeks to anticipate and delineate the assessments offered by both parents and teachers concerning a child’s behavior and overall functioning with the Behavior Rating Inventory of Executive Function-2 (BRIEF-2). Mothers, fathers, and teachers of 59 children diagnosed or in the process of being assessed for ADHD participated in this study. The responses provided by 59 mothers, 59 fathers, and 57 teachers to the BRIEF-2 questionnaire were collected. The performance of various feature selection techniques, including Lasso, decision trees, random forest, extreme gradient boosting, and forward stepwise regression, was evaluated. The results indicate that Lasso stands out as the optimal method for our dataset, striking an ideal balance between accuracy and interpretability. A repeated validation analysis reveals an average positive correlation exceeding 0.5 between the inattention/hyperactivity scores reported by informants (mother, father, or teacher) and the predictions derived from Lasso. This performance is achieved using only approximately 18% of the BRIEF-2 items. These findings underscore the usefulness of variable selection techniques in accurately characterizing a patient’s condition while employing a small subset of assessment items. This efficiency is particularly valuable in time-constrained settings and contributes to improving the comprehension of ADHD.

There is an urgent need to identify effective drugs for the treatment of nerve injury caused by unconjugated bilirubin (UCB). Our previous research found that cystatin C (CST3) alleviates UCB-induced neurotoxicity by promoting autophagy in nerve cells, but that autophagy inhibitors did not completely inhibit the effects of CST3. This study investigated whether CST3 could alleviate the neurotoxicity of UCB by promoting the secretion and transport of exosomes containing UCB to the liver for metabolism. It demonstrated that hyperbilirubinemia mice treated with CST3 had a higher number of serum exosomes than those in hyperbilirubinemia mice treated with phosphate-buffered saline. CST3-mediated protection against UCB-induced damage was abolished when autophagy and extracellular vesicle inhibitors were used in combination. The number of exosomes in the CST3 overexpression group was higher than that in the control group. Molecular docking experiments showed that UCB and CST3 had high docking score (−8.2). These results suggest that UCB may be excreted from cells by exosomes, and CST3 may promote this process by binding to UCB and entering the exosomes. We demonstrated that the effect of CST3 relied on liver cells with normal UDP-glucuronyl transferase1A1 (UGT1A1) activity in a coculture system of HT22 and L02 cells. CST3 levels were lower in exosomes secreted by L02 cells than in those secreted by human umbilical vein endothelial cells (HUVECs), whereas CST3 levels were higher in the culture supernatants of L02 cells than in the culture supernatants of HUVECs. This suggests that UCB exosomes in L02 cells may be released and internalized by CST3 and that UCB is then processed by UGT1A1 to conjugate UCB, thus reducing its toxicity. These results suggest that CST3 might alleviate UCB-induced neurotoxicity by promoting the clearance of UCB from cells via exosomes and that these effects are dependent on UGT1A1 activity in liver cells.

Background Neuropathic pain is a common symptom of Guillain–Barré syndrome (GBS). The infiltration of macrophages in the dorsal root ganglion (DRG) contributed to neuropathic pain in nerve injury. The underlying mechanisms of neuropathic pain in patients with GBS remain unknown. Experimental autoimmune neuritis (EAN) is a useful mice model of GBS. Our study aimed to explore whether the infiltration of macrophages in DRG is associated with neuropathic pain of EAN. Methods Male C57BL/6 mice were randomly divided into two groups, the EAN group ( n = 12) and the control group ( n = 12). Six mice in each group were sacrificed after anesthetization in the attack and remission phase, respectively. The 50% paw withdrawal threshold and clinical score were measured, and macrophages with its subtypes were detected in the spleen and DRG tissue. Results More macrophages infiltrated the DRG of the EAN group in the attack phase and mostly surrounded neurons in the DRG. The proportion of macrophages and pro-inflammatory macrophages in the spleen of mice with EAN was significantly higher than the control group in the attack phase. Conclusion The infiltration of macrophages in DRG might be associated with neuropathic pain of EAN and pro-inflammatory macrophages may involve in neuropathic pain of EAN.

Introduction Depression, the leading cause of disability worldwide, is known to be exacerbated by severe acute respiratory syndrome coronavirus 2 infection, worsening coronavirus disease 2019 (COVID-19) outcomes. However, the mechanisms and treatments for this comorbidity are not well understood. Methods This study utilized Gene Expression Omnibus datasets for COVID-19 and depression, combined with protein–protein interaction networks, to identify key genes. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to understand gene functions. The CIBERSORT algorithm and NetworkAnalyst were used to examine the relationship of immune cell infiltration with gene expression and to predict transcription factors (TFs) and microRNAs (miRNAs) interactions. The Connectivity Map database was used to predict drug interactions with these genes. Results TRUB1 , PLEKHA7 , and FABP6 were identified as key genes enriched in pathways related to immune cell function and signaling. Seven TFs and nineteen miRNAs were found to interact with these genes. Nineteen drugs, including atorvastatin and paroxetine, were predicted to be significantly associated with these genes and potential therapeutic agents for COVID-19 and depression. Conclusions This research provides new insights into the molecular mechanisms of post-COVID-19 depression and suggests potential therapeutic strategies, marking a step forward in understanding and treating this complex comorbidity.

Functional magnetic resonance imaging (fMRI) stands as a pivotal tool in advancing our comprehension of Schizophrenia, offering insights into functional segregations and integrations. Previous investigations employing either task-based or resting-state fMRI primarily focused on large main regions of interest (ROI), revealing the thalamus and superior temporal gyrus (STG) as prominently affected areas. Recent studies, however, unveiled the cytoarchitectural intricacies within these regions, prompting a more nuanced exploration. In this study, resting-state fMRI was conducted on 72 schizophrenic patients and 74 healthy controls to discern whether distinct thalamic nuclei and STG sub-regions exhibit varied functional integrational connectivity to main networks and to identify the most affected sub-regions in Schizophrenia. Employing seed-based analysis, six sub-ROIs – four in the thalamus and two in the STG – were selected. Our findings unveiled heightened positive functional connectivity in Schizophrenic patients, particularly toward the anterior STG (aSTG) and posterior STG (pSTG). Notably, positive connectivity emerged between the medial division of mediodorsal thalamic nuclei (MDm) and the visual network, while increased functional connectivity linked the ventral lateral nucleus of the thalamus with aSTG. This accentuated functional connectivity potentially influences these sub-regions, contributing to dysfunctions and manifesting symptoms such as language and learning difficulties alongside hallucinations. This study underscores the importance of delineating sub-regional dynamics to enhance our understanding of the nuanced neural alterations in Schizophrenia, paving the way for more targeted interventions and therapeutic approaches.

The limitation of artificial intelligence (AI) large language models to diagnose diseases from the perspective of patient safety remains underexplored and potential challenges, such as diagnostic errors and legal challenges, need to be addressed. To demonstrate the limitations of AI, we used ChatGPT-3.5 developed by OpenAI, as a tool for medical diagnosis using text-based case reports of multiple sclerosis (MS), which was selected as a prototypic disease. We analyzed 98 peer-reviewed case reports selected based on free-full text availability and published within the past decade (2014–2024), excluding any mention of an MS diagnosis to avoid bias. ChatGPT-3.5 was used to interpret clinical presentations and laboratory data from these reports. The model correctly diagnosed MS in 77 cases, achieving an accuracy rate of 78.6%. However, the remaining 21 cases were misdiagnosed, highlighting the model’s limitations. Factors contributing to the errors include variability in data presentation and the inherent complexity of MS diagnosis, which requires imaging modalities in addition to clinical presentations and laboratory data. While these findings suggest that AI can support disease diagnosis and healthcare providers in decision-making, inadequate training with large datasets may lead to significant inaccuracies. Integrating AI into clinical practice necessitates rigorous validation and robust regulatory frameworks to ensure responsible use.

Motor commands are transmitted from the motor cortical areas to effectors mostly via the corticospinal (CS) projection. Several subcortical motor nuclei also play an important role in motor control, the subthalamic nucleus, the red nucleus, the reticular nucleus and the superior colliculus. These nuclei are influenced by motor cortical areas via respective corticofugal projections, which undergo complex adaptations after motor trauma (spinal cord/motor cortex injury) or motor disease (Parkinson), both in the absence or presence of putative treatments, as observed in adult macaque monkeys. A dominant effect was a nearly complete suppression of the corticorubral projection density and a strong downregulation of the corticoreticular projection density, with the noticeable exception in the latter case of a considerable increase of projection density following spinal cord injury, even enhanced when an anti-NogoA antibody treatment was administered. The effects were diverse and less prominent on the corticotectal and corticosubthalamic projections. The CS projection may still be the major efferent pathway through which motor adaptations can take place after motor trauma or disease. However, the parallel supraspinal motor corticofugal projections may also participate in connectional adaptations supporting the functional recovery of motor abilities, representing potential targets for future clinical strategies, such as selective electrical neurostimulations.

Spinal cord injury (SCI) is a severe medical condition that affects millions of people worldwide each year. In Iran, an estimated 9 out of every 100,000 individuals experience traumatic SCI occurrences. Long-term disabilities and comorbidities stemming from SCI often necessitate multiple therapeutic interventions. The aim of this study is to evaluate the morbidity in Iranian SCI patients. In this study, a four-step process was used to select, extract, analyze, and synthesize relevant literature. The search covered 750 records from five databases, resulting in 25 articles included in the review. These articles, published between 2000 and 2023, utilized cross-sectional, qualitative, or cohort designs. The findings explored the prevalence, risk factors, and consequences of comorbidities associated with SCI, categorized into four themes: physical, sexual, psychological, and metabolic morbidity. Physical morbidity refers to medical conditions or complications affecting body functions or structures in SCI patients. The most frequently reported cases include pressure ulcers, pain, osteoporosis, fractures, impaired pulmonary function, renal failure, and obesity. Metabolic morbidity includes conditions such as vitamin D deficiency and cardiometabolic risk factors. Psychological morbidity encompasses depression, anxiety, and adjustment disorders. Sexual morbidity refers to conditions or complications affecting the sexual function or satisfaction of SCI patients. This narrative literature review offers a comprehensive examination of various aspects of SCI in Iranian patients. The review identifies numerous challenges and difficulties faced by SCI patients while also highlighting protective factors that can improve their well-being. Additionally, the review acknowledges gaps and limitations within the current literature and suggests possible avenues for future research.

Parkinson’s disease (PD) is a neurodegenerative disorder that predominantly affects dopaminergic neurons in the substantia nigra and ventral tegmental area, resulting in symptoms such as tremors, muscle rigidity, bradykinesia, and potential cognitive and affective disturbances. The effective delivery of pharmacological agents to the central nervous system is hindered by various factors, including the restrictive properties of the blood‒brain barrier and blood‒spinal cord barrier, as well as the physicochemical characteristics of the drugs. Traditional drug delivery methods may not provide the therapeutic concentrations necessary for functional restoration in PD patients. However, lipid-based nanoparticles (NPs) offer new possibilities for enhancing the bioavailability of established treatment regimens and developing innovative therapies that can modify the course of the disease. This review provides a concise overview of recent advances in lipid-based NP strategies aimed at mitigating specific pathological mechanisms relevant to PD progression. This study also explores the potential applications of nanotechnological innovations in the development of advanced treatment modalities for individuals with PD.

Humans live under constant threat from pathogenic microorganisms and minimizing such threat has been a major evolutionary selective force in shaping human behavior and health. A particular adaptive mechanism against the harm caused by parasites and their infectiousness is disgust sensitivity, which has evolved to detect and avoid poisonous foods as well as bodily secretions harboring virulent microorganisms. This ubiquitous and reflexive behavior requires the integration of several internal and external sensory signals between the brain, the autonomic nervous system (ANS), and the gastrointestinal tract. Although the emotional expression of disgust is experienced by almost all individuals, the neural mechanisms of sensory signals underlying disgust sensitivity may differ in certain psychiatric conditions. Psychopathy, for instance, is a personality disorder in which disgust sensitivity to contagious bodily secretions is apparently absent or downregulated from its atypical personality temperament. In this review, we provide convergent behavioral, anatomical, and cellular evidence to suggest that a fractured experience of disgust sensitivity might be an additional feature of psychopathic behavior. First, we discuss the neural networks of certain brain regions mediating the emotional states of disgust and then discuss the intersection of the ANS and gastrointestinal tract in the processing of disgust and its relevance to aberrant antisocial behavior. Together, this work highlights the interconnections between the brain and the bilateral body plan as an integrated cell network that is relevant for understanding common principles underlying function and dysfunction of disgust levels in psychiatric domains.

Objective Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown. Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID. Methods In this study, MMP-9 was measured in the serum of long COVID patients and healthy controls, as well as in the supernatant fluid of cultured human microglia cell line stimulated by recombinant severe acute respiratory syndrome coronavirus 2 Spike protein, as well as lipopolysaccharide (LPS) and neurotensin (NT) used as positive controls. MMP-9 was measured by commercial enzyme-linked immunosorbent assay. Results MMP-9 was significantly elevated in the serum of long COVID patients compared to healthy controls. Moreover, there was significant release of MMP-9 from a cultured human microglia cell line stimulated by LPS, NT, or Spike protein. We further show that pretreatment with the flavonoids luteolin and tetramethoxyluteolin (methlut) significantly inhibited the release of MMP-9 stimulated by the Spike protein. Conclusion MMP-9 from Spike protein-stimulated microglia could contribute to the development of long COVID and may serve as a target for treatment including the use of luteolin.

Background: The objective of this study (registered under number 2020 006) was to assess the internal consistency of the revised Mental Health Professional Culture Inventory (MHPCI) scale, which comprises 15 items, among mental health service workers in Romania. Methods: To examine the psychometric properties of the MHPCI questionnaire within the Romanian population, we employed two main methods: The partial credit model (PCM) and Exploratory factor analysis (EFA). Results: A total of 94 individuals were interviewed, and among them, 71 provided complete responses to the questionnaire. All 15 items demonstrate a strong fit with the PCM, as indicated by mean-square (MSQ) outfit and MSQ infit values falling within the range of 0.5 to 1.5. But items 3 and 11 exhibit MSQ values greater than 1.5, suggesting that it may be challenging to predict individuals’ responses to these items. The KMO index stands at 0.7, surpassing the recommended threshold of 0.6, signifying an acceptable level of suitability. Nevertheless, only 59.3% of the total variance is accounted for by the first four factors, and these factors do not align with the dimensions identified in the original article. Conclusion: The internal structure of the Romanian version of the MHPCI demonstrates satisfactory psychometric properties. These properties will need to be further validated through additional studies conducted in diverse socio-cultural contexts.