Mechanistic insights into compatibility-based detoxification of Fengshi Gutong Capsules through network toxicology and in vivo validation.

Ameliorative potential of pomegranate juice against synthetic colorant (E124)-induced biochemical and histopathological changes in the rat brain and testes.

In silico docking and in vivo assessment of Mondia whitei fruit extract in attenuating CdCl2-Induced neurodegeneration in rat.

Astrocyte-derived exosomes in cognitive recovery: A comparative assessment of neurobehavioral, molecular, and electrophysiological dimensions.

A ferulic acid derivative FAD012 protects brain microvascular endothelial cells from H2O2-induced ferroptosis via NRF2 activation.

While antisense oligonucleotide (ASOs) therapies have emerged as promising tools to modulate gene expression in neurological diseases, these new agents face challenges in the context of the central nervous system, particularly regarding distribution and duration of action. Translational approaches that enable the tracking of ASO effects in the whole brain are therefore needed to guide their preclinical and clinical development. In the present study, we used PET imaging as a translational tool to study the pharmacodynamics of an ASO targeting a metabotropic receptor, namely, the dopamine D2 receptor. We selected an ASO sequence directed toward D2 mRNA in the rat brain and optimized its chemical backbone by a gapmer design. This anti-D2R ASO was administered directly into the striatum of adult rats via intracerebral stereotaxic injection at different doses. The longitudinal pharmacodynamic effects of the ASO were assessed using successive PET acquisitions with the D2R radiotracer [11C]raclopride to quantify changes in D2R receptor expression in the striatum. Our PET findings indicated a reduction of D2R availability from 3 weeks to 10 weeks postinjection. The apomorphine-induced rotation test confirmed that the postsynaptic striatal dopaminergic imbalance was behaviorally relevant and persisted for three months after the ASO injection. This work provides novel insights into the potential of PET neuroimaging to explore the in vivo efficacy and longevity of modified ASOs delivered directly into the brain, opening translational applications.

Phosphatidylcholines (PCs), which differ in fatty acyl chain lengths and degrees of unsaturation, often exist as complex mixtures of isomeric and isobaric compounds. Accurate structural identification of these lipids in imaging mass spectrometry (IMS) is essential for contextualizing their spatial distributions within tissue biochemistry. Gas-phase charge inversion ion/ion reactions offer a powerful approach to improve lipid identification by converting precursor ion types prior to dissociation, yielding more structurally informative fragmentation patterns. Herein, we employ a novel multiply charged reagent ion, 1,2,4,5-tetrakis(4-carboxylphenyl)benzene (TCPB), to perform charge inversion ion/ion reactions with protonated PC analytes. The use of higher reagent charge states improves the kinetics of the ion/ion reaction, reducing the time required for reactions to occur within an imaging experiment. Additionally, the use of higher reagent charge states results in more exothermic reactions, which facilitates consecutive fragmentation of ion/ion reaction complexes to the desired fatty acyl product ions without the need for supplemental activation, further improving the speed and efficiency of this process. This optimized workflow is applied in imaging mass spectrometry experiments to spatially map PC 34:1 isomers within rat brain tissue, revealing distinct spatial distributions for PC 16:0/18:1 and PC 18:1/16:0. These results underscore the importance of isomer resolution in lipid imaging and demonstrate the potential for exploiting reaction kinetics to improve ion/ion reaction isomer and isobar separation in imaging applications.

Thymidine phosphorylase (TP) expression is increased in neurons under ischemia/reperfusion (I/R) conditions. Our aim was to evaluate the effect of tipiracil hydrochloride (TPI), a selective TP inhibitor, on rat brain tissue subjected to I/R. Both common carotid arteries were occluded for 30min in the ischemic untreated group of rats (C-IR), and ischemic groups treated with tipiracil 25mg/g (T-IR25) or 50mg/kg (T-IR50). In the control group (C), the arteries were not ligated. Tipiracil was given during ischemia, and after 8h of I/R intraperitoneally. After 24h of I/R, brain tissue was isolated for histology and immunohistochemy of TP expression. Metalloproteinases 2 and 9 (MMP-2 and -9) and tissue inhibitor of metalloproteinases (TIMP-1) were determined in serum at 3 and 24h of reperfusion. TP expression in brain tissue was the highest in C-IR and T-IR25 compared to the C and T-IR50. No changes in serum TP levels were observed. After 24h, there was a significant decrease in MMP-9 levels in T-IR25 compared to the C-IR and T-IR50. MMP-2 levels also decreased significantly at this time point in all groups compared to group C, which correlated with increased TIMP-1 activity in the T-IR25 and T-IR50. The inhibition of TP activity in the group receiving TPI suggests its protective effect on brain tissue under I/R conditions. The decrease in MMP activities in the treated groups suggests a protective effect of TPI on the development of neuroinflammation caused by local brain tissue ischemia.

This study employed Fourier Transform Infrared (FTIR) and Raman microspectroscopy to investigate the long-term biochemical effects of prenatal exposure to a ketogenic diet (KD) on the developing rat brain. KD, high in fat and low in carbohydrates, shifts metabolism from glucose to ketone utilization and is widely used to treat drug-resistant epilepsy. Given its potential use in pregnant women, understanding KD impact on offspring neurodevelopment is critically important. By combining the complementary strengths of FTIR and Raman microspectroscopy, this study enabled the detection of subtle biochemical changes within brain tissue of animals fed prenatally with KD. Spectroscopic analyses revealed region- and sex-dependent alterations, primarily involving metabolism of lipids and phosphate-containing compounds─key components of myelin and cellular membranes. Most changes were observed in 60-day-old males prenatally exposed to KD. Creatine- and cholesterol-rich inclusions were detected in hippocampal and cortical regions, possibly reflecting maladaptive outcomes of altered energy metabolism and/or neuroadaptive mechanisms related to metabolic preconditioning. Furthermore, these males exhibited reductions in multiple lipid-associated FTIR parameters, which potentially reflecting disruptions in oligodendrocyte function or myelination dynamics. While 30-day-old females from experimental group showed region-specific lipid decreases and elevated phosphate-related ratios, these changes largely normalized by 60 days, indicating developmental stabilization of metabolic effects after prenatal KD exposure. In contrast to males, females showed no creatine or cholesterol inclusions, likely reflecting sex-specific modulation. Estrogens regulate creatine metabolism, support mitochondrial and antioxidant function, and modulate lipid homeostasis, providing neuroprotection and mitigating metabolic disturbances.

Mechanism of Shanhu Qishiwei pills in regulating endoplasmic reticulum stress through GRP78/CHOP signaling pathway for the treatment of cerebral ischemia.

Neonatal hypoxic-ischemic encephalopathy (NHIE) is a leading cause of morbidity and mortality in term infants. The anesthetic dexmedetomidine (Dex) has been shown to reduce brain damage. In this study, hypoxia-ischemia (HI) in neonatal rats caused significant cerebral infarction, neurological deficits, learning and cognitive impairments, inflammatory responses, and microglia polarization. Dex treatment mitigated HI-induced brain injury in rats. Lipopolysaccharide (LPS) increased inflammation in BV2 cells, elevated M1 polarization markers, and raised the proportion of M1 cells. Dex reduced inflammation and M1 polarization in BV2 cells. Rbm47 was identified as a target of Dex, being downregulated in NHIE rat brain tissues and upregulated by Dex. Rbm47 co-localized with microglia and was decreased as the microglia marker Iba-1 increased. Adenovirus-mediated overexpression of Rbm47 alleviated brain injury in NHIE rats and reduced microglial inflammation and M1 activation, both invitro and invivo. Conversely, knockdown of Rbm47 hindered the protective effects of Dex against BV2 cell inflammation and M1 polarization. This study indicates that Rbm47 mediates the protective effects of Dex against NHIE brain injury.

ABSTRACT Objectives Paradoxical sleep deprivation (PSD) elicits oxidative-inflammatory stress, causing neuro-behavioral impairment. Dietary cyanidine-3-O-glucoside (C3G) alleviates oxidative-inflammatory stress-associated brain damage. This study, for the first time, explored whether C3G provides a preventive influence against behavioral deficits and hippocampal/prefrontal oxidative–inflammatory changes in PSD rats and the possible involvement of tryptophan catabolism. Methods Wistar rats were divided into control, PSD + fluoxetine-treated (10 mg/kg), PSD + C3G (50 mg/kg), PSD + C3G (100 mg/kg), and C3G (100 mg/kg) groups (n = 8). After three weeks of PSD/REM-selective paradigm (7am – 7pm), using modified multiple platform technique (MMP), behavioral analyses were conducted for cognitive, anxiety, and depressive-like behavior; subsequently, animals were sacrificed, and the brain sections (hippocampus and prefrontal cortex) were excised for biochemical and histology analyses. In silico analyses for the interaction of C3G and indoleamine 2,3-dioxygenase (IDO) was conducted. Results C3G treatment prevented alterations in behavioral indices, cortical and hippocampal histological damage, purinergic and acetylcholine hydrolysis, oxidative-inflammatory stress, and tryptophan catabolism, caused by PSD. The in-silico investigations accentuated the C3G and tryptophan catabolism enzyme (IDO) interaction. Conclusion C3G protects the PSD rat brain regions by preventing oxidative stress, inflammation, and mitigating hydrolysis of ATP and AMP, in addition to regulating IDO activity/expression to alleviate behavioral impairment and alterations in histological features of the cortical and hippocampal regions of the brain.

Neuroprotective effects of honokiol against hexavalent chromium exposure in rat brain: Evidence from oxidative stress, inflammation, and apoptosis.

Monitoring biochemical processes requires tools to detect specific molecular species in vivo. Although responsive probes detectable by MRI enable this, conventional MRI contrast agents often lack sufficient sensitivity. Here we circumvent this limitation using nanoscale probes constructed from pore-forming peptides incorporated into paramagnetic liposomes. In our design, target molecules control MRI contrast by regulating water access to liposome-encapsulated gadolinium chelators. The large ratio of gadolinium complexes to pores provides a sensitivity gain by over an order of magnitude compared with small-molecule MRI sensors. We demonstrate the probe architecture using biotin as a model analyte and gramicidin A as the basis for responsive pores. We then validate the biotin-sensitive liposomal probes in vitro and in rat brain, and we show that minimally invasive delivery to multiple tissue types is feasible. Furthermore, we identify pore sequences that provide greater MRI contrast effects than native gramicidin and we demonstrate that further channel modifications permit detection of different target molecules. This work thus introduces a potent and engineerable technology for molecular imaging in living systems.

This study evaluated the neuroprotective effects of pomegranate peel polyphenols (PPEP) and their nanoparticles in a rodent model of DOX-induced neurotoxicity. Polysorbate 80- coated PPEP poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP) were synthesized by the double emulsification solvent evaporation technique. Successful encapsulation of PPEP was confirmed by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), and Differential Scanning Calorimetry (DSC) analyses. Neurotoxicity was induced in male Wistar rats by administering DOX (2.5mg/kg bw) once every five days i.p. Treatment with PPEP and its nanoparticles (10mg/kg bw equivalent polyphenols p.o) was performed for 60 days. At the end of the treatment, the Morris water maze test was performed to assess cognitive function, and rat brains were removed for further histopathological, biochemical, and molecular analyses. To understand the pathophysiology of DOX-induced neurodegeneration, oxidative stress, inflammatory, and apoptosis markers were assessed by ELISA and Western blotting. Treatment with an encapsulated pomegranate peel polyphenolic extract reduced oxidative stress as evidenced by increased catalase and superoxide dismutase levels and decreased malondialdehyde levels. Mechanistically, it alleviated inflammation by downregulating the expression of pro-inflammatory markers NF-kB (p65) and TNF-α; restored acetylcholine levels, and reduced apoptosis markers (caspase 3 and cytochrome c). Furthermore, histopathological findings supported the attenuation of DOX-induced pathologies in the hippocampus and cortex regions of the brain. Enhanced bioavailability and efficacy of polyphenols were observed for the encapsulated extract. Our results demonstrate the neuroprotective potential of free and encapsulated PPEP in DOX-induced neurotoxicity and highlight the effective valorization of pomegranate peel waste for health applications.

Brain injury disrupts tissue integrity, creating wounds with complex boundaries that hinder effective repair. Regeneration and reconnection require guiding deformed tissue along proper growth pathways. Pre-engineered scaffold implants made from biomaterials offer promise; however, while hydrogel-based scaffolds are common for brain repair, their low mechanical strength and slow cell growth limit effectiveness. This study examined solid scaffolds, which provide superior mechanical support and promote rapid cell growth, to modulate the growth behavior of injured hippocampal tissue. Three scaffold types were used: planar bioactive glass, planar aragonite (promoting neuronal and astrocytic growth), and three-dimensional glass beads. The scaffolds were applied in two steps. First, hippocampal tissue chunks from postnatal rat brains were cultured on the planar substrates; then, glass beads were added. On glass, tissue adopted a round/oval shape with pronounced vertical growth, while on aragonite it flattened and spread irregularly, reaching lengths twice as large and an area 3.8 times greater than on glass. In the second step, adding glass beads led to vertical growth on glass, with tissue encapsulating beads to form a complex 3D structure. In contrast, aragonite-supported tissue formed bump-like structures when encapsulating the beads, remaining largely planar. Also, they showed a tenfold lower bead density and twofold greater inter-bead distances than tissue on glass. In both cases, cellular outgrowth occurred. These findings show that sequential application of solid scaffolds with distinct structural properties can guide diverse tissue growth behaviors and serve as a strategy for fabricating neural implants, with implications for treating brain trauma and disease.

An Icariin-Loaded PCL Electrospun Scaffold for Enhanced Tendon-Bone Healing in Rotator Cuff Repair.

Adenosine as a signalling molecule modifies blood-brain barrier (BBB) tightness in pathological conditions. Our aim was to investigate the direct and polarized effects of adenosine on the BBB using co-culture and in vivo models. The expression of adenosine receptors was measured by qRT-PCR. BBB models were prepared from primary rat brain endothelial cells, pericytes and glial cells and were treated with adenosine and A2A receptor antagonist SCH-58261 in the luminal and abluminal compartments. Barrier function in cultures was tested by impedance kinetics, electrical resistance and fluorescein permeability. Acute effects of intracardiac or intracerebroventricular adenosine were measured on the BBB permeability for fluorescein in the brain cortex and hippocampus of rats and mice. Adenosine receptors were present in BBB cells and brain endothelial cells expressed predominantly A2A receptors. Adenosine exerted a polarized effect on both in vitro and in vivo models; it tightened the paracellular barrier from the luminal side and increased fluorescein permeability from the abluminal or brain side. The abluminal, but not the luminal effect, was observed in sleep and in sleep deprivation. Based on the receptor profile, the results of co-culture experiments and the blocking effects of SCH-58261, the effect is mainly mediated luminally on brain endothelial, abluminally on brain endothelial and pericyte adenosine receptors. Adenosine had a polarized circadian effect on BBB permeability, from the luminal side tightened the barrier in culture models and in vivo, whereas it opened the barrier from the abluminal side.

Current magnetic resonance imaging (MRI) requires the subject to remain stationary to limit motion artifacts and avoid unwanted field-induced brain stimulation. However, imaging during large-scale motion could enable studies in which motion itself is central. One example is the study of brain networks involved in vestibular function, which senses head motion. Here, we demonstrate Moving MRI (mMRI), a system that enables imaging during large-scale motion by moving the subject and scanner together to minimize relative motion. We implemented a proof-of-concept platform using a compact, cryogen-free superconducting magnet mounted on a pneumatically actuated tilt mechanism that moves the magnet, gradients, and RF coil as a unit during scanning. Phantom and in vivo rat brain scans were acquired during repetitive tilting. We characterized artifacts arising from tilt-induced field shifts and residual subject-scanner motion, and partially reduced these effects. mMRI enables imaging during large-scale movement and may broaden access to naturalistic vestibular paradigms while providing a foundation for future human systems.

This study aimed to evaluate whether chemical exchange saturation transfer (CEST) imaging, in combination with the nonionic X-ray iodinated contrast agent Iobitridol, can detect extracellular pH (pHe) in rats with gliomas and enable the construction of quantitative pHe maps. CEST pH imaging was performed both on Iobitridol phantoms and on rat models bearing brain gliomas, using a 7.0 Tesla small animal MRI scanner (Agilent Technologies) and employing varying radiofrequency (RF) powers (1.5, 3.0, and 6.0 µT) based on the ratio of apparent exchange-dependent relaxation (AREXratio) technique (specifically, 1.5/6.0 µT and 3.0/6.0 µT). The results indicated that AREXratio can more effectively eliminate the influence of magnetization transfer (MT) effects from the CEST signal, thereby enabling more accurate quantification of pH. In vivo CEST pHe imaging distinctly delineated the glioma regions, and quantitative analysis demonstrated that the mean extracellular pH values within gliomas were closely aligned and exhibited an acidic profile. These results further verify the reliability and accuracy of CEST imaging for quantitative assessment of the tumor microenvironment's acidity in gliomas. In conclusion, this study is the first to demonstrate that non-invasive CEST imaging can accurately detect the acidic extracellular microenvironment of brain gliomas and produce quantitative pHe maps with good spatial resolution, highlighting its significant potential for clinical translation.