Search Results (749)

Callistemon citrinus has shown antioxidant and anti-inflammatory properties in certain tissues. However, its impact on the brain remains unproven. This study investigates the effect of C. citrinus extract and phytosomes on the oxidative status of the brains of rats fed a high-fat–fructose diet (HFD). Fifty-four male Wistar rats were randomly divided into nine groups (n = 6). Groups 1, 2, and 3 received a standard chow diet; Group 2 also received the vehicle, and Group 3 was supplemented with C. citrinus extract (200 mg/kg). Groups 4, 5, 6, 7, 8, and 9 received a high-fat diet (HFD). Additionally, groups 5, 6, 7, 8, and 9 were supplemented with orlistat at 5 mg/kg, C. citrinus extract at 200 mg/kg, and phytosomes loaded with C. citrinus at doses of 50, 100, and 200 mg/kg, respectively. Administration was oral for 16 weeks. Antioxidant enzymes, biomarkers of oxidative stress, and fatty acid content in the brain were determined. A parallel artificial membrane permeability assay (PAMPA) was employed to identify compounds that can cross the intestinal and blood–brain barriers. The HFD group (group 4) increased body weight and adipose tissue, unlike the other groups. The brain fatty acid profile showed slight variations in all of the groups. On the other hand, group 4 showed a decrease in the activities of antioxidant enzymes SOD, CAT, and PON. It reduced GSH level, while increasing GPx activity as well as MDA, 4-HNE, and AOPP levels. C. citrinus extract and phytosomes restore the antioxidant enzyme activities and mitigate oxidative stress in the brain. C. citrinus modulates oxidative stress in brain tissue through 1.8-cineole and α-terpineol, which possess antioxidant and anti-inflammatory properties. Full article

Background: Acute mountain sickness (AMS) is a prevalent and potentially life-threatening condition caused by rapid exposure to high-altitude hypoxia, affecting pulmonary and neurological functions. Tongqiao Jiuxin Oil (TQ), a traditional Chinese medicine formula composed of aromatic and resinous ingredients such as sandalwood, agarwood, frankincense, borneol, and musk, has been widely used in the treatment of cardiovascular and cerebrovascular disorders. Clinical observations suggest its potential efficacy against AMS, yet its pharmacological mechanisms remain poorly understood. Methods: The chemical profile of TQ was characterized using UHPLC-Q-Exactive Orbitrap HRMS. Network pharmacology was applied to predict the potential targets and pathways involved in AMS. A rat model of AMS was established by exposing animals to hypobaric hypoxia (~10% oxygen), simulating an altitude of approximately 5500 m. TQ was administered at varying doses. Physiological indices, oxidative stress markers (MDA, SOD, GSH), histopathological changes, and the expression of hypoxia- and apoptosis-related proteins (HIF-1α, VEGFA, EPO, Bax, Bcl-2, Caspase-3) in lung and brain tissues were assessed. Results: A total of 774 chemical constituents were identified from TQ. Network pharmacology predicted the involvement of multiple targets and pathways. TQ significantly improved arterial oxygenation and reduced histopathological damage in both lung and brain tissues. It enhanced antioxidant activity by elevating SOD and GSH levels and reducing MDA content. Mechanistically, TQ downregulated the expression of HIF-1α, VEGFA, EPO, and pro-apoptotic markers (Bax/Bcl-2 ratio, Caspase-3), while upregulated Bcl-2, the anti-apoptotic protein expression. Conclusions: TQ exerts protective effects against AMS-induced tissue injury by improving oxygen homeostasis, alleviating oxidative stress, and modulating hypoxia-related and apoptotic signaling pathways. This study provides pharmacological evidence supporting the potential of TQ as a promising candidate for AMS intervention, as well as the modern research method for multi-component traditional Chinese medicine. Full article

Hibiscus sabdariffa (Hs) is a tropical plant with a wide range of therapeutic properties; however, few studies have evaluated its potential adverse effects. In the present study, the cytotoxic and genotoxic effects of the hydroalcoholic extract of Hs (EHHs) dried calyces administered during gestation were assessed in Wistar rats and their newborns using the micronucleus assay in peripheral blood and the quantification of malondialdehyde (MDA) in various tissues. Three different doses of EHHs (500, 1000, and 2000 mg/Kg) were administered orally to five pregnant Wistar rats per group during the final days of gestation (days 16–20). Blood samples were collected every 24 h during the last six days of gestation and from the neonates at birth, along with tissue samples for MDA quantification. EHHs induced myelosuppression in the mothers and genotoxicity in their newborns, as well as cytotoxicity, evidenced by increased MDA levels in serum, liver, and kidneys of the mothers, and in the liver, kidneys, brain, and muscle tissues of the neonates. These findings provide important insights into the safety profile of Hs, and its use is therefore recommended only under the supervision of a qualified healthcare professional. Full article

Diffuse axonal brain injury (DAI) is a common, debilitating consequence of traumatic brain injury, yet its detection and severity grading remain challenging in clinical and experimental settings. This study evaluated the sensitivity of diffusion tensor imaging (DTI), histology, and neurological severity scoring (NSS) in assessing injury severity in a rat model of isolated DAI. A rotational injury model induced mild, moderate, or severe DAI in male and female rats. Neurological deficits were assessed 48 h after injury via NSS. Magnetic resonance imaging, including DTI metrics, such as fractional anisotropy (FA), relative anisotropy (RA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD), was performed prior to tissue collection. Histological analysis used beta amyloid precursor protein immunohistochemistry. Sensitivity and variability of each method were compared across brain regions and the whole brain. Histology was the most sensitive method, requiring very small groups to detect differences. Anisotropy-based MRI metrics, especially whole-brain FA and RA, showed strong correlations with histology and NSS and demonstrated high sensitivity with low variability. NSS identified injury but required larger group sizes. Diffusivity-based MRI metrics, particularly RD, were less sensitive and more variable. Whole-brain FA and RA were the most sensitive MRI measures of DAI severity and were comparable to histology in moderate and severe groups. These findings support combining NSS and anisotropy-based DTI for non-terminal DAI assessment in preclinical studies. Full article

Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using multiplex electrochemiluminescence and western blot. Differentially expressed genes (DEGs) were identified by RNA sequencing, and elastic net modeling was used to define exposure-predictive gene signatures. CBN exposure altered inflammatory biomarkers across tissues, with activation of nuclear factor kappa B (NF-κB) signaling. In the lung, gene set enrichment revealed activated pathways related to proliferation and inflammation, while epithelial–mesenchymal transition (EMT) and oxidative phosphorylation were suppressed. In the brain, EMT, inflammation, and senescence pathways were activated, while ribosomal function and oxidative metabolism were downregulated. Elastic net modeling identified a lung gene signature predictive of CBN exposure, including Kcnq3, Tgfbr1, and Tm4sf19. These findings demonstrate that inhalation of a surrogate burn pit mixture induces inflammatory and metabolic gene expression changes in both lung and brain tissues, supporting the utility of this animal model for understanding systemic effects of airborne military toxicants and for identifying potential biomarkers relevant to DRRD and Veteran health. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

The postmortem interval (PMI), defined as the time elapsed between death and the discovery or examination of the body, is a crucial parameter in forensic science for estimating the time of death. There are many ways to measure the PMI, such as Henssge’s nomogram, which uses rectal temperature measurement; livor mortis; rigor mortis; and forensic entomology. However, these methods are usually affected by various conditions in the surrounding environment. The purpose of the present study was to compare molecular genetics and histological changes in the brain and skeletal muscle tissues of SD rats over increasing periods of time after death. For the PMIs, we considered 0 h, 6 h, 12 h, 24 h, 36 h, 48 h, 4 days, 6 days, 8 days, 10 days, 14 days, and 21 days and compared them at 4 °C and 26 °C. Hematoxylin and Eosin (H&E) staining was performed to observe tissue changes. Morphological tissue changes were observed in cells for up to 21 days at 4 °C, and cell destruction was visually confirmed after 14 days at 26 °C. Total RNA (tRNA) was isolated from each tissue sample, and complementary DNA (cDNA) was synthesized. A reverse transcription quantitative PCR (RT-qPCR) SYBR Green assay targeting three types of housekeeping genes, including Gapdh, Sort1, B2m, and 5S rRNA, was performed. The results showed that Gapdh and 5S rRNA were highly stable and could be better RNA targets for estimating the PMI in brain and skeletal muscle tissues. Conversely, Sort1 and B2m showed poor stability and low expression levels. In conclusion, these molecular biomarkers could be used as auxiliary indicators of the PMI in human, depending on the stability of the marker. Full article

Glaucoma is a trans-synaptic neurodegenerative disease, and the pathological increase in intraocular pressure (IOP) is a major risk factor of glaucoma. High IOP alters microstructure and morphologies of the brain tissue. Since mechanical properties of the brain are sensitive to the alteration of the tissue microstructure, we investigate how varying durations of chronic elevated IOP alter brain mechanical properties. A chronic high IOP rat model was induced by episcleral vein cauterization with subconjunctival injection of 5-Fluorouracil. At 2, 4 and 8 weeks after induction, indentation tests were performed on the brain slices to measure mechanical properties in the hippocampus, lateral geniculate nucleus and occipital lobe of both hemispheres. Meanwhile, the brain’s microstructure was assessed via F-actin and myelin staining. Compared to the blank control group, the Young’s modulus decreased in all three brain regions in the highIOP experimental groups. F-actin fluorescence intensity and myelin area fraction were reduced in the hippocampus, while β-amyloid levels and tau phosphorylation were elevated in the experimental groups. Our study provides insight into Alzheimer’s disease pathogenesis by demonstrating how chronic high IOP alters the brain’s mechanical properties. Full article

Background and Objectives: Alzheimer’s disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer’s disease-like model (AD), Alzheimer’s disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis. Full article

Cadmium (CAD) is a prevalent environmental contaminant that poses serious cardiotoxic risks. The heart, kidney, liver, and brain are just a few of the essential organs that can sustain serious harm from CAD, a very poisonous heavy metal. The cardiotoxic mechanism of CAD is linked to oxidative damage and inflammation. A trace element with anti-inflammatory, anti-apoptotic, and antioxidant qualities, selenium (SEL) can be taken as a dietary supplement. The biotoxicity of heavy metal CAD is significantly inhibited by SEL, a mineral that is vital to human and animal nutrition. Through ROS-induced PARP-1/ADPR/TRPM2 pathways, this study seeks to assess the preventive benefits of selenium against cardiovascular damage caused by CAD. The SEL showed encouraging results in reducing inflammatory and oxidative reactions. Rats were given 0.5 mg/kg SEL and 3 mg/kg 2-Aminoethyl diphenylborinate (2-APB) intraperitoneally for five days, in addition to 25 mg/kg CAD given via gavage. Histopathological examination findings revealed that the morphologic changes in the hearts of the CAD group rats were characterised by marked necrosis and the degeneration of myocytes and congestion of vessels. Compared to the rats in the CAD group, the hearts of the SEL, 2-APB and SEL+2-APB groups showed fewer morphological alterations. Moreover, in rats given CAD, there was an increase in cardiac malondialdehyde (MDA), total oxidant (TOS), reactive oxygen species (ROS), caspase (Casp-3-9), and TNF-α, whereas glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant (TAS) decreased. SEL improved antioxidants, avoided tissue damage, and reduced cardiac MDA, TOS, and ROS. In rats given CAD, SEL decreased cardiac PARP-1, TRPM2, TNF-α, and caspase. In summary, by reducing oxidative stress and cardiac damage and modifying the ROS/PARP-1/TRPM2 pathway, SEL protected against CAD cardiotoxicity. Full article

Blast-induced polytrauma (BIPT) is a common injury among military personnel exposed to explosive blasts. It is increasingly recognized as a complex, multisystem disorder that extends beyond neurological damage to include systemic metabolic and inflammatory dysfunction. Adipokines, particularly leptin and adiponectin, are hormones secreted by adipose tissue and are emerging as key mediators in the pathophysiology of traumatic brain injuries. Yet, their long-term dynamics following blast exposure remain unclear. This study investigated the temporal profiles of plasma leptin and adiponectin in a longitudinal rat model of BIPT. Adult male Sprague Dawley rats were subjected to either a single (B) or repeated (BB) blast exposure (20 psi) or served as sham controls. Plasma samples were collected at 24 h, 1 month, 6 months, and 12 months post-exposure, and adipokine levels were measured using Enzyme-linked Immunosorbent Assay. Adiponectin levels exhibited a biphasic response: both B and BB groups showed significant early decrease at 24 h and 1 month compared to sham animals, followed by robust elevation at 6 and 12 months, particularly in the repeated blast group. In contrast, leptin levels remained unchanged acutely but rose significantly at 6 and 12 months post-blast, with the BB group again showing the highest levels. These patterns indicate sustained, exposure-dependent dysregulation of adipokine signaling after blast trauma. The study provides the first longitudinal profile of systemic adipokine responses to BIPT, revealing their potential as accessible biomarkers and therapeutic targets. These findings support a model of chronic metabolic and inflammatory imbalance in BIPT and warrant further investigation in human cohorts and mechanistic studies. Full article

Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5–10 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel–Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel–Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood–brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances. Full article

Background: Tramadol binds to opioid receptors and inhibits norepinephrine and serotonin reuptake, causing serotonin syndrome. Tianeptine stimulates serotonin reuptake and reduces serotonin levels. The aim of this study was to investigate whether tianeptine is effective against serotonin syndrome that may occur with serotoninergic drugs such as tramadol and citalopram. Methods: Rats were divided into eight groups (n = 6) that received tramadol (50 mg/kg), citalopram (10 mg/kg), or tianeptine (5 mg/kg) alone or a combination of tramadol + citalopram, tramadol + tianeptine, citalopram + tianeptine or tramadol + citalopram + tianeptine at the same doses administered to the stomach by oral gavage for 3 weeks. The healthy control group was given saline. Malondialdehyde, total glutathione, superoxide dismutase, and catalase levels were measured in removed brain tissues. The tissues were also examined histopathologically. Results: In the tramadol, tramadol + citalopram, and tramadol + citalopram + tianeptine groups, malondialdehyde levels were found to be higher compared to the control group, while glutathione, superoxide dismutase, and catalase levels were found to be lower. In other groups, values close to the control group were measured. Morphological degeneration was observed in neurons in the tramadol + citalopram group. The swelling of astrocytes and pericellular edema in oligodendrocytes were also observed. A significant population increase was noted in microglial cells. Blood vessels belonging to the tissue were observed to be severely dilated and congested. Histopathological damage was partially resolved in the group given tramadol + citalopram + tianeptine. Conclusions: The tramadol + citalopram combination caused severe oxidative stress in brain tissue. Tramadol alone caused mild damage in brain tissue, whereas tianeptine prevented the brain damage caused by tramadol. Full article

The hypothalamic-pituitary-adrenal (HPA) axis plays an important regulatory role in inflammatory responses to systemic or local infection in the host. A high-calorie diet, which can aggravate pediatric pneumonia and delay recovery, is intimately associated with HPA axis disorder; however, its underlying mechanisms remain unknown. This study examined whether the mechanism by which a high-calorie diet aggravates pneumonia is related to HPA axis disorder. In this study, juvenile rats were fed a high-calorie diet and/or nebulized with lipopolysaccharide (LPS) for model construction. Our data shows that a high-calorie diet increases interleukin-1 beta(IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels in lung tissues and aggravates LPS-induced inflammatory injury in the lungs of juvenile rats. Additionally, we found that a high-calorie diet decreases the expression level of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in juvenile rats with pneumonia, resulting in HPA axis disorder. Hypothalamus proteomics and Western blot results proved that a high-calorie diet upregulated the expression level of hypothalamus hypoxia-inducible factor-1 alpha (HIF-1α) in juvenile rats with pneumonia, and this mechanism is associated with reduced HIF-1α ubiquitination. We further observed that HPA axis disorder was significantly abated and inflammatory damage in rat lung tissues was significantly alleviated after in vivo HIF-1α pathway inhibition. This shows that pneumonia aggravation by a high-calorie diet is associated with interference in the HIF-1α-mediated HPA axis. A high-calorie diet boosts HIF-1α signaling in the hypothalamus and exacerbates LPS-induced pneumonia by disrupting the HPA axis. This sheds light on lung inflammation and strengthens the lung-brain connection. Full article

Methionine restriction (MetR) is a dietary intervention that extends mean and maximum life span in rodents, at least in part, by reducing oxidative stress and promoting DNA stability in different tissues. Regarding DNA stability, DNA repair pathways play a critical role, both in the nuclear and mitochondrial fractions. Base excision repair (BER) is the main one involved in the repair of oxidative damage, as well as the main one in mitochondria. Despite the relevance of DNA repair in DNA maintenance, it is not known whether MetR regulates BER as a mechanism of preserving genomic stability. In this study we analyzed, for the first time, the effect of 40% MetR for 7 weeks on BER in rat brain cortex and liver, focusing on the expression of several key BER genes. In the brain cortex, MetR significantly increased the gene expression of the DNA glycosylase Ogg1 and the DNA endonuclease Ape1 while reducing DNA polymerase γ gene expression. Conversely, MetR led to a general reduction in the expression of BER genes in the liver. Our findings highlight a tissue-specific regulation of the BER gene expression in response to MetR. Different potential mechanisms underlying these changes in BER, such as DNA methylation or activation of signaling pathways, are discussed. Full article