The gut microbiota-brain axis constitutes a dynamic, bidirectional communication network that integrates neural, endocrine, immune, and metabolic pathways to regulate host physiology and behavior. Accumulating evidence indicates that disturbances within this axis have been consistently associated with metabolic, autoimmune, and neuropsychiatric disorders; however, much of the current evidence, particularly from human studies, remains largely correlative, and causal relationships are still under active investigation, highlighting its systemic relevance to health and disease. This review synthesizes current understanding of the structural and functional components of the gut microbiota-brain axis, including microbial community dynamics, neural signaling pathways, and key endocrine and immune mediators. We examine mechanistic insights into how microbial-derived metabolites influence brain function, cognition, mood regulation, stress responses, and disease pathogenesis. In addition, we discuss emerging therapeutic strategies targeting the gut microbiota-brain axis, including psychobiotics and fecal microbiota transplantation, while acknowledging dietary approaches, such as prebiotic supplementation, fiber-rich diets, and fermented food consumption, as complementary strategies that modulate microbiota composition that may indirectly support gut-brain axis function. By integrating mechanistic, clinical, and translational perspectives, this review aims to clarify current knowledge gaps and highlight future directions for leveraging the gut microbiota-brain axis in personalized approaches to neuropsychiatric disease management.
Brain metastases from small cell lung cancer (SCLC) are characterized by high malignancy and poor prognosis. Emerging evidence demonstrates that combining brain radiotherapy (BRT) and immunotherapy may improve outcomes; however, the optimal strategy for combining these therapies remains undefined. This study was conducted to evaluate the efficacy and safety of concurrent BRT combined with tislelizumab and chemotherapy in patients with SCLC and brain metastases. Patients with treatment-naive or previously treated SCLC and brain metastases who were admitted to Zhejiang Cancer Hospital (Hangzhou, China) between September 2023 and November 2025 were enrolled. All patients received one cycle of chemotherapy combined with tislelizumab, followed by initiation of BRT within one week. Chemotherapy plus immunotherapy was subsequently continued, followed by maintenance immunotherapy until disease progression. The primary endpoint was intracranial objective response rate (iORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and treatment-related adverse events (TRAEs). Twenty-five patients were included. Among them, the iORR was 76.0%, and intracranial DCR was 100.0%. The systemic ORR and DCR were 56.0% and 80.0%, respectively. The median OS was 11.1 months [95% confidence interval (CI): 7.4-14.8], the median PFS was 5.6 months (95% CI: 3.1-8.1), and the median intracranial PFS was 7.6 months (95% CI: 5.7-9.5). TRAEs of any grade were identified in all patients, while grade ≥3 adverse events were found in 36.0% of patients. Hematological toxicity was most common (88.0%). Concurrent BRT combined with tislelizumab and chemotherapy demonstrated promising intracranial and systemic efficacy with manageable toxicity in SCLC patients with brain metastases and warrants further validation in larger prospective studies.
Brainstem metastasis from small-cell lung cancer (SCLC) is exceedingly rare and is associated with a dismal prognosis. This study presents a case of brainstem metastasis from SCLC treated with the TMEp-CI-M platform, achieving no evidence of disease (NED) for more than 20 months. The TMEp-CI-M platform is designed to overcome resistance in immunologically "cold" tumors through sequential tumor microenvironment priming (TMEp), checkpoint inhibition (CI), and microbiome modulation. We have previously reported its efficacy in pancreatic neuroendocrine carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, non-small cell lung cancer (NSCLC), and colorectal cancer. A 60-year-old male with programmed death ligand 1 (PD-L1)-negative extensive-stage small-cell lung cancer (ES-SCLC) and brainstem metastasis received the TMEp-CI-M regimen. The TMEp phase integrated stereotactic body radiotherapy (SBRT), low-dose etoposide, and anlotinib, followed by CI with the programmed death 1 (PD-1)/cytotoxic T lymphocyte antigen 4 (CTLA-4) bispecific antibody cadonilimab and concurrent probiotic supplementation. The patient's pro-gastrin-releasing peptide (ProGRP) level normalized after the first cycle (from 1803 pg/mL to 23.71 pg/mL) during a total of 6 treatment cycles. At the time of this report (20 months after treatment initiation), the patient remains NED, with only Grade 1 hypothyroidism as an adverse event. The TMEp-CI-M platform may enhance the efficacy of immunotherapy in ES-SCLC, enabling durable responses even in patients with brainstem metastases. Although this platform has demonstrated promise across multiple tumor types, further prospective and mechanistic studies are warranted to confirm its clinical utility.
Brain tumours are a commonly diagnosed solid cancer in children and young adults. Many survivors experience long-term complications. We conducted a systematic review to assess the effectiveness of outpatient rehabilitation interventions in reducing long-term complications following childhood brain tumours. Three databases were searched to November 2024. Two reviewers independently screened studies, assessed quality, and extracted data. Outcomes were categorised as primary [functional, psychological and Quality of Life (QoL)] and secondary (social, cognitive and sleep disturbance). Eight papers were included. Most studies evaluated physical therapy interventions, assessing changes in functional outcomes, which were associated with the greatest proportion of significant improvements (p ≤ 0.05). Varying effects were seen for psychological, QoL, and social outcomes. Cognitive outcomes did not show significant improvements following cognitive, academic and exercise-based interventions. Although studies reported positive functional, psychological, QoL and social outcomes, following various interventions, clear conclusions of the long-term effectiveness of rehabilitation interventions cannot be made. Further research is needed with longer-term follow-up, so effective rehabilitation strategies can be determined for this population. Better research could help develop interventions at a health-system level that could improve function, perceived wellbeing, and QoL of children and young people with brain tumours.
Brain graph classification from resting-state fMRI (rs-fMRI) can support the identification of neurological conditions and inform personalized analysis. Here, we present a hierarchical sparse spatiotemporal graph neural network (STGNN)-GLNSTGNN-to address sparse feature selection in spatiotemporal brain graph classification. We evaluated GLNSTGNN on two rs-fMRI datasets comprising 1,956 participants with 200 regions of interest (ROIs) and 12 subnetworks after standardized preprocessing. GLNSTGNN applies GroupLassoNet-based hierarchical sparsity to select informative features, while combining spatial graph convolution on a fixed functional connectivity adjacency with temporal convolution on time-varying BOLD signals to capture spatial dependencies and temporal dynamics. Across multiple baselines, GLNSTGNN showed improved discriminative performance and consistent ROI selection, supporting interpretable subnetwork-level patterns. These results suggest that integrating hierarchical sparsity with spatiotemporal graph learning can provide a practical framework for robust and interpretable brain graph classification.
To evaluate the differences in olfactory function, volumes of brain regions related to olfaction, and subregion volumes of the amygdala and hippocampus among the healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD), as well as the association of volumes and olfactory function. Clinical data for the participants included age, gender, education level, Mini-Mental State Examination (MMSE). Participants underwent olfactory function test, including three sub-experiments as namely threshold test (TT), discrimination test (DT) and identification test (IT) and brain magnetic resonance imaging (MRI), including a three dimensions T1-weighted sequence (3D-T1WI). The brain subregions were extracted automatically by the uAI research portal. A total of 107 participants were recruited, including 35 HC, 28 MCI and 44 AD. The volumes of hippocampal subregion (HC_Body_L and HC_Tail_L) were significant difference in HC and MCI groups while the global hippocampal volumes were not. All tested domains (TOS, TT, DT, and IT) showed statistically significant differences in olfactory function between the three groups. Furthermore, we found only IT showed significant differences across all three pairwise comparisons among the HC, MCI, and AD groups. The hippocampus and amygdala volumes showed the strongest correlation with olfactory function, followed by the PHG, PCC, lOFC and ERC, and more sub-region volumes had moderate-strength correlations with DT, IT, and TOS, according to Spearman correlation analysis. The olfactory function and the volumes of the hippocampal subnuclei maybe good candidates as early biomarkers of preclinical AD.
Brain development during adolescence and early adulthood coincides with shifts in emotion regulation and sleep. Despite this, few existing datasets simultaneously characterize affective dynamics, sleep variation, and multimodal measures of brain development. Here, we describe the study protocol and initial release (n = 10) of an open data resource of neuroimaging paired with densely sampled behavioral measures in adolescents and young adults. All participants complete multi-echo functional MRI, compressed-sensing diffusion MRI, and advanced arterial spin-labeled MRI. Behavioral measures include ecological momentary assessment, actigraphy, extensive cognitive assessments, and detailed clinical phenotyping focused on emotion regulation. Raw and processed data are openly available without a data use agreement and will be regularly updated as accrual continues. Together, this resource will accelerate research on the links between mood, sleep, and brain development.
Lung adenocarcinoma (LUAD) frequently leads to brain metastasis (BM), representing a significant clinical challenge associated with poor patient outcomes. While the tumor microenvironment (TME) is known to influence progression, the specific immune cell programs and mechanisms underpinning cross-organ metastatic evolution remain incompletely defined. In this study, we systematically mapped cellular composition and macrophage-state transitions to investigate the functional remodeling of tumor-associated macrophages (TAMs), specifically dissecting the CD74High TAM subpopulation throughout the metastatic process. We reanalyzed a published single-cell RNA-sequencing dataset (GSE131907) comprising LUAD primary lung tumors (LTs) and LUAD with BMs. Following standardized preprocessing, cell-type annotation, and inferCNV-based inference of the copy number variation (CNV)-somatic gains or losses of large DNA segments used to identify malignant cells-we reconstructed ligand-receptor networks using CellChat. The TAM population was integrated across organs to perform differential expression analysis, pathway enrichment, AUCell activity scoring, GeneNMF-based meta-program discovery, and pseudotime trajectory reconstruction to delineate TAM evolution. Our analysis revealed that the TME retained several conserved communication modules across organs, among which the APP-CD74 axis remained highly active and preferentially associated with CD74High TAMs. However, functional states diverged significantly by tissue site. CD74High TAMs in LT exhibited immune-clearance features enriched for phagosome, antigen processing, and transendothelial migration programs. In contrast, brain-metastatic CD74High TAMs displayed a coordinated attenuation of phagocytosis-associated programs, accompanied by heightened inflammatory signaling, metabolic reprogramming, and stress-adaptation states. GeneNMF and pseudotime analyses delineated a continuous evolutionary trajectory wherein CD74High TAMs emerged from a lung-resident-like program, transitioned through a lipid-associated intermediate, and culminated in terminal SPP1+ hypoxic and inflammatory phenotypes. Our study identifies CD74High TAMs as a highly plastic macrophage population that undergoes systematic cross-organ functional remodeling during LUAD BM. The observed loss of phagocytic capacity reflects dynamic functional state transitions toward an inflammatory and hypoxic phenotype rather than the passive enrichment of a single subpopulation. These insights provide a single-cell evolutionary framework for metastasis-associated immune reprogramming and underscore the potential of CD74 as a target for therapeutic intervention.
Brain abscess is a rare but life-threatening intracranial infection most commonly resulting from hematogenous dissemination or contiguous spread. Pulmonary infections, including bronchiectasis, may represent a potential source of systemic infection. We report the case of a 50-year-old woman with type 2 diabetes mellitus admitted for acute hypoxemic respiratory failure secondary to severe bronchiectasis-associated infection complicated by acute respiratory distress syndrome (ARDS). Respiratory samples identified Streptococcus pneumoniae and Influenza A virus. Blood cultures remained negative. The patient initially improved under empirical antibiotic therapy but subsequently developed neurological deterioration on hospital day 5, characterized by seizures and nystagmus. Brain magnetic resonance imaging (MRI) revealed multiple bilateral cerebral abscesses with ring enhancement and diffusion restriction consistent with pyogenic abscesses. Transthoracic echocardiography showed no evidence of infective endocarditis, although transesophageal echocardiography was not performed. Despite escalation of antimicrobial therapy and intensive care management, the patient developed refractory septic shock and multiorgan failure, resulting in death.
Brain endurance training (BET), a training approach that integrates cognitively demanding tasks with physical exercise, has received increasing attention in recent years. A growing body of evidence indicates that mental fatigue can impair athletic performance, executive functions, and sport-specific skills. However, a comprehensive synthesis of the overall effects of BET on both physical and cognitive performance is still lacking. Therefore, this systematic review aimed to evaluate the effects of BET on physical performance, sport-specific performance, and cognitive outcomes. A systematic search was conducted in PubMed, Web of Science, SPORTDiscus, Embase, the Cochrane Library, and Scopus. Controlled longitudinal intervention studies investigating the effects of BET interventions were included. In total, 13 controlled trials met the inclusion criteria. The intervention duration ranged from 4 to 12 weeks, with BET protocols typically combining cognitively demanding tasks (e.g., Stroop task, Go/No-Go task, AX-CPT task, and working memory paradigms) with endurance training, resistance training, or sport-specific training. The results indicate that BET consistently improves endurance-related outcomes, including time to exhaustion, time-trial performance, intermittent endurance, and sustained muscular endurance. However, these improvements are generally not accompanied by significant changes in traditional peripheral physiological markers such as maximal oxygen uptake, blood lactate concentration, or heart rate. In contrast, the effects of BET on maximal strength and repeated sprint ability appear limited or inconsistent. Improvements in sport-specific performance appear to be task-dependent and are more pronounced under conditions of mental fatigue. Most included studies reported beneficial effects of BET on cognitive performance, particularly in terms of faster reaction times and enhanced resistance to performance decrements under mentally fatiguing conditions. However, improvements in baseline cognitive performance under fresh conditions were less consistent across studies. Overall, BET may enhance endurance and cognitive performance primarily through central regulatory mechanisms rather than peripheral physiological adaptations by increasing individuals' tolerance to mental fatigue. However, given the heterogeneity of intervention protocols and the generally moderate methodological quality of the included studies, these findings should be interpreted with caution. Future research should further investigate dose-response relationships and the long-term adaptations associated with BET. Systematic review registation: https://inplasy.com/inplasy-2026-1-0050/, identifier INPLASY (registration number INPLASY202610050).
Children with pediatric brain tumors (PBT) follow a unique clinical course as diverse morbidities may emerge during treatment and may even persist into survivorship. Effectively addressing their needs requires joined efforts from various providers in order to provide optimal support. To investigate the challenges and needs of providers working in pediatric oncology with PBT patients and survivors. Providers with experience working with PBT patients were recruited throughout France to participate in a semi-structured interview. Data were analyzed following a reflexive thematic analysis method. 48 providers were interviewed, with a total of 46 participants included in the final study. Main challenges and needs were identified through 6 themes addressing the strained care environment, the triangular relationship with patients and their family, the complex needs of PBT patients, the emotional burden of care, the long journey of the care pathway, and coordination aspects. Main challenges encompassed poor communication among care teams, as well as patient-provider communication. Repeatedly facing poor prognoses and end-of-life situations were also identified as emotional challenges by providers. Participants also mentioned the necessity to decrease administrative task load, to increase the development of multidisciplinary care, and that training regarding specific PBT care needs is essential for providing optimal care. Pediatric neuro-oncology represents a unique and emotionally demanding field. Despite persistent communication and coordination challenges, findings highlight the critical importance of dedicated, well-coordinated multidisciplinary teams and long-term follow-up care to meet the complex needs of PBT patients and their families.
Male breast cancer is rare, accounting for less than 1% of all breast cancers, and central nervous system (CNS) metastases are an uncommon but poor prognostic manifestation. The aim of the current case report is to discuss a 50-year-old man with stage IV estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancer who presented with new-onset focal neurological deficits and was found to have a solitary left parietal brain metastasis with vasogenic edema and midline shift. He underwent gross total resection via craniotomy, with pathology confirming metastatic ductal carcinoma consistent with the primary tumor. Postoperatively, he received adjuvant stereotactic radiosurgery (30-35 Gy in five fractions) to the resection cavity and was transitioned from tamoxifen to trastuzumab deruxtecan (T-DXd) for improved CNS-directed systemic therapy. Surveillance imaging at 6 months demonstrated no intracranial recurrence, and systemic restaging showed no extracranial disease progression. This case highlights the importance of prompt neuroimaging for new neurological symptoms in male breast cancer patients and supports a multimodal strategy, including surgical resection, focal radiation, and CNS-penetrant HER2-targeted therapy, for achieving durable intracranial control in select patients with isolated brain metastasis.
Three-dimensional assessment of fetal cortical morphology from MRI is essential for understanding early brain neurodevelopment. However, measurement can be affected by fetal imaging quality, number and selection of available stacks, and reconstruction methods. We evaluated the within-session reliability of an automated cortical morphometry pipeline in 30 typically developing fetuses [22-36 weeks gestational age (GA)]. For each subject, two disjoint subsets of 2D T2-weighted stacks (no shared stacks) were independently reconstructed into 3D volumes using the Neural Slice-to-Volume Reconstruction (NeSVoR) and the Slice-to-Volume Reconstruction Toolkit (SVRTK). Cortical plate volume, surface area, mean sulcal depth, and absolute mean curvature were extracted, and measurement reliability was assessed using absolute percent difference (APD) and intraclass correlation coefficients (ICC). Multiple linear regression evaluated the effects of mean stack quality, quality difference between subsets, stack count, and GA on measurement reliability. NeSVoR-derived metrics showed high reliability for all measures (mean APD < 3%, ICC > 0.99). SVRTK-derived metrics were also robust (mean APD < 5%, ICC > 0.97). Reliability increased with greater stack count and older GA in NeSVoR, and with higher mean stack quality in SVRTK. These results demonstrate that automated cortical morphometry from fetal MRI yields highly consistent measurements of volumetric and surface metrics within the proposed within-session design, once minimum levels of image quality and stack count are met. This study proposes a within-session benchmark for automated fetal cortical measurements and underscores that systematic reliability assessment is essential for confident application of automated pipelines in fetal neuroimaging.
Brain and central nervous system cancers are a major cause of cancer-related morbidity and mortality in children. However, evidence on long-term trends and inequalities across Asia remains limited. Using Global Burden of Disease 2023 data, we analyzed the burden among children aged 0-14 years in Asia from 1990 to 2023 and projected trends to 2050. Age-standardized incidence, mortality, and disability-adjusted life year (DALY) rates were lower in 2023 than in 1990, but no significant regional trends were observed. Substantial geographical heterogeneity persisted, with higher burdens in Central and Western Asia. Infants bore the highest burden, and boys had higher incidence and mortality than girls. Inequality analyses indicated persistent concentration of burden in lower-socio-demographic index settings. Projections suggested a continued decline in overall burden to 2050 but with considerable uncertainty. These findings highlight persistent regional and socio-economic disparities and require strengthened early diagnosis, treatment access, and survivorship care in resource-limited settings.
Purpose The aim of this retrospective single-center study was to evaluate the safety and efficacy of palliative intra-arterial chemoperfusion (IAC) for patients diagnosed with recurrent or post-therapeutic progressive symptomatic lung cancer brain metastases (LCBM). Materials and methods A total of 10 patients (five women and five men; median age: 56 years (range: 40-80 years)) with recurrent or post-therapeutic LCBM were included. Chemotherapy consisted of either carmustine or a combination of mitomycin C, gemcitabine, and cisplatin. The radiological follow-up was performed using magnetic resonance imaging (MRI) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The overall survival (OS) was calculated using the Kaplan-Meier method. Results All patients were treated with prior systemic therapy, and seven patients additionally received radiation therapy. A total of 37 sessions of IAC (3.7/patient) were performed. No major complications occurred. The mean sum of the longest diameter (SLD) was 4.5±1.2 cm for all patients prior to treatment. The mean SLD for patients with radiological follow-up was 3.9±2.1 cm after treatment. Four patients (4/8) developed progressive disease. Three patients (3/8) achieved stable disease, and one patient (1/8) showed complete response. None of the patients had partial response. Two patients (2/10) were not assessable due to loss of radiological imaging post-interventional. The mean OS time was 9.7 months (95% CI: 2.4-17.0). Conclusion Although IAC seems to be a safe approach for palliative patients with recurrent or post-therapeutic progressive symptomatic LCBM, further studies with a larger patient population are needed to confirm its efficacy.
Long COVID is increasingly associated with disruption in brain homeostasis, manifesting as severe neurological dysfunction, brain fog and cognitive impairment. This present study investigated localised cognitive deficits in long COVID patients by examining brain blood oxygenation-level-dependent (BOLD) signal activity using ultra-high-field 7 T (7T) task-based functional magnetic resonance imaging (fMRI). Whole-brain BOLD signal differences were assessed across 19 long COVID patients, and 27 healthy controls (HC) including 12 COVID-recovered (Cov-RHC) and 15 COVID-19-naïve HC (nHC). 225 fMRI volumes were acquired during the Stroop colour-word task. Functional and anatomical images were processed using SPM12 to extract the BOLD signal intensity time course from whole-brain voxels for inferences between cohorts during task-fMRI. Significantly low BOLD activation in long COVID patients was observed compared to Cov-RHC in the anterior cingulate cortex (p = 0.002, cluster size=650, Z-value = 4.67), and the precuneus (p = <0.001, cluster size = 1893, Z-value = 4.67). Furthermore, BOLD intensities in precuneus showed a negative association with self-reported pain scores (p = 0.040) and the duration of illness (p = 0.03) in long COVID patients, suggesting significant correlation between BOLD signal and an increase in duration of illness and pain levels. No statistically significant BOLD differences were observed for inter-group comparisons between nHC vs. long COVID, and nHC vs. Cov-RHC. Response times to incongruent (p = 0.002) and congruent task stimuli (p = 0.001) significantly varied between nHC and long COVID cohorts, demonstrating overall faster information processing by nHC. Reduced BOLD signals to 'core' brain regions in long COVID imply reduced cognitive control by intrinsic networks that mediate information processing, cognitive and executive functions due to perturbations linked to cerebral blood flow, oxygenation status, and ongoing neuroinflammation.
Tuberculous meningitis (TBM) is the most severe form of central nervous system (CNS) tuberculosis and carries significant morbidity, particularly when diagnosis is delayed. Cranial nerve involvement is a recognized complication, most frequently affecting the abducens nerve (CN VI); bilateral oculomotor nerve (CN III) palsy, however, is exceedingly rare and typically signifies pathology at the level of the midbrain. The oculomotor nerve originates from paired nuclei in the midbrain tegmentum at the level of the superior colliculus; any compressive or inflammatory lesion at this site can produce bilateral CN III deficits. We report a 70-year-old man with type 2 diabetes mellitus presenting with subacute fever, headache, and altered sensorium, who subsequently developed bilateral ptosis with ophthalmoplegia. The brain MRI demonstrated multiple disseminated tuberculomas with a focal midbrain lesion at the oculomotor nuclear-fascicular complex and communicating hydrocephalus. This case highlights an uncommon neuro-ophthalmological manifestation of TBM and emphasizes the critical role of early clinico-radiological correlation in diagnosis and management.
The amygdala is the nucleus of the brain that is largely responsible for perceiving danger and plays a role in emotion, behavior, control and learning. A small amygdala has been associated to aggression. Horned ewes are expected to be more aggressive and have a smaller amygdala. Both horned and hornless ewes exhibit intraspecific head-butting behavior and both species are at risk for traumatic brain injury. The aim of this study was to investigate the neuronal density, glial cells and blood-brain barrier (BBB) of the amygdala in horned and hornless ewes. Four horned and six hornless ewe heads (age: 16.00 ± 4.00 months) were obtained from the abattoir. The brains were carefully removed and preserved in 10.00% formalin for 5 days. Bilateral amygdalae were sectioned. The samples were stained with Hematoxylin and Eosin, immunohistochemical (glial fibrillary acidic protein) and Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling methods, and the histological structures of the amygdala were examined by light microscopy. The Mann-Whitney U test was used to analyze the data. Neuronal density was estimated to be 143,230 ± 12,540 per mm3 in horned and 152,230 ± 18,430 per mm3 in hornless ewes. Horned subjects had reduced numbers of neurons, damaged BBB and localized inflammatory areas. More apoptotic neurons were observed in horned ewes. Further studies are needed to determine whether these differences in neuronal density, glial cells, and BBB are acquired (due to trauma) or congenital. The results of this study might need further similar studies to be conducted in the future.
Glioblastoma (GBM) is the most aggressive form of malignant brain cancer. Here, we synthesized two chimeric peptide-based radiopharmaceuticals (Comb-1 and Comb-2) targeted to the membrane-bound form of heat shock protein 70 (mHsp70), which is overexpressed in GBM tissues, for future theranostic applications. The design concept features a DOTA chelator for coordination to different radiometals tethered directly or via a PEG linker to a chimeric peptide. The latter combines the Hsp70-targeting ability of the TPP sequence with the blood-brain barrier (BBB) penetration of another 7-amino acid sequence (d-PepH3) derived from the dengue virus capsid protein (DEN2C). The two compounds were successfully radiolabelled with gallium-67, suitable for single photon emission computed tomography (SPECT) imaging, or with lutetium-177 for β- therapy. Furthermore, the in vitro properties of the ligand, including lipophilicity (log D 7.4), human serum albumin (HSA) binding, and stability in human serum were evaluated. The presence of the TPP sequence affected the half-life of the combinatorial peptides. Cytometry assays performed with a fluorescent analogue of Comb-2 confirmed the binding to mHsp70-expressing U87-MG cells. In an in vitro model, all tracers demonstrated the ability to cross the BBB, indicating that conjugation of the mHsp70-targeting peptide to the PepH3 sequence did not impair its translocating properties. Biodistribution experiments with 67Ga-labeled compounds were performed in naive female CD1 mice and showed brain uptake at 2 min p.i., as well as renal excretion. For the best performing compound [67Ga]Ga-Comb-2 (0.60 ± 0.17% IA g-1 (injected activity per gram)), the biodistribution experiment was also performed with perfusion of the organs after sacrifice, and the results showed retention of radioactivity in the brain (0.14 ± 0.05% IA g-1). Further metabolic studies in murine urine and blood were performed after biodistribution, confirming the stability of the chimeric tracers.
A seizure is a neurological disorder in the brain that is caused by changes in the function of brain neurons. Caffeic acid phenetyl ester (CAPE), as a polyphenol, has antioxidant, anti-inflammatory, and anticancer effects. Since the effects of CAPE on the neurotoxins and neurotoxic medicinal agents have not been widely investigated, this study aimed to investigate the effect of CAPE on the nicotine (NIC)-induced seizures in mice. Thirty-three male mice were divided into five groups of 6-8 as follows: sham group (normal saline), NIC group (5 mg/kg single dose on day 7), treatment groups (CAPE at 4 and 8 mg/kg for 7 days), and diazepam group (1 mg/kg single dose on day 7). At the end, the animals were anesthetized, and mortality, convulsive behavior, total thiol, thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and the expression of nuclear factor kappa B (NF-kB) protein in the brain frontal cortex were measured, and histological studies were performed. Treatment with CAPE decreased the levels of TBARS, TNF-α, and NO and increased the levels of total thiol, CAT, SOD, GPx, and NF-kB protein expression compared to the NIC group. Seizure behavioral tests and histopathological investigations confirmed these results. According to the antioxidant effects of CAPE in various studies, it seems that CAPE can improve seizures by reducing inflammation and inhibiting oxidative stress.