Brain Tissue Damage Research Articles

Magnetic Targeting Nanocarriers Combined with Focusing Ultrasound for Enhanced Intracerebral Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mortality around the world, and surgery is still the most direct and effective way to remove ICH. However, the potential risks brought by surgery, such as normal brain tissue damage, post-operative infection, and difficulty in removing deep hematoma, are still the main problems in the surgical treatment of ICH. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) is reported to show a good therapeutic effect in hematoma clearance. Herein, a magnetic targeting nanocarrier loaded with a PPARγ agonist (15d-PGJ2-MNPs) is synthesized, which could be magnetically targeted and enriched in the area of the hematoma after intravenous injection. Subsequent application of focusing ultrasound (FUS) could enhance drug diffusion, which activates the PPARγ receptors on macrophages around the hematoma for better hematoma clearance. The 15d-PGJ2-MNP treatment alleviates brain injury, accelerates hematoma clearance, attenuates neuroinflammation, reduces brain edema and significantly improves the deficits in sensory and motor function and spatial learning ability in the ICH mouse model. This work proposes an effective magnetic targeting plus FUS method to treat ICH, highlighting its great potential in the treatment of hemorrhagic stroke.

Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications. A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells. A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated. In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.

Toxicologic effect of short-term enrofloxacin exposure on brain of Carassius auratus var. Pengze

To further explore short-term exposure of enrofloxacin (ENR) induced toxicity in crucian carp brain that has been reported by our previous work, as well as the possible toxicological mechanisms, this study investigated the blood-brain barrier (BBB) permeability to low dosage of ENR through comprehensively assessing expression of BBB constitutive molecules zonula occludens-1 (ZO-1) and permeability glycoprotein (P-gp), as well as ENR residue in brain of crucian carp. Toxicologic effect of ENR on brain tissue was determined through evaluating expression of brain-derived proteins S100B, neuron specific enolase (NSE) and glial fibrillary acidic protein (GFAP) in crucian carp brain tissue, as well as contents of the proteins in serum. The toxicological mechanisms were explored through analyzing transcriptome analysis data. Results showed that ENR possessed excellent permeability to crucian carp BBB, which was closely related to deranged BBB structure and declined ENR efflux that were attributed to downregulated expression of ZO-1 and P-gp by ENR exposure. Meanwhile, S100B, NSE and GFAP were upregulated in brain by ENR, and came out into blood across the damaged BBB. These data revealed that ENR induced disruption of BBB and damage of brain tissue in crucian carp. Transcriptome analysis data indicated that ENR induced toxicologic effect might be related to modification of metabolism, organismal systems, and genetic information processing, etc., and that PI3K/Akt, MAPK, HIF-1, and ubiquitin mediated proteolysis involved the mechanisms, most of the mechanisms were attributed to ENR induced oxidative stress in crucian carp brain.

Neuro-protective effects of n-butylphthalide on carbon monoxide poisoning rats by modulating IL-2, AKT and BCL-2.

Acute carbon monoxide poisoning (CO-poisoning) causes neurotoxicity by inducing necrosis, apoptosis, lipid peroxidation, and oxidative stress. DL-3-n-butylphthalide (NBP) is a synthetic compound originally extracted from the seeds of Chinese celery and based on pure l-3-n-butylphthalide. In ischemia/reperfusion, it exerts neuroprotective effects through its anti-apoptotic, anti-necrotic and antioxidant properties, and activation of pro-survival pathways. Our study performed bioinformatic analysis to identify the differential expression genes. CO-poisoning patients' blood was collected to confirm the findings. Male rats were exposed to CO 3000 ppm for 40 min, and NBP (100 mg/kg/day) was continuously injected intraperitoneally immediately after poisoning and for the next 15 days. After NBP treatment, the rats were evaluated by Morris water maze test. At the end of experiments, blood and brain tissues of the rats were collected to evaluate the expression levels of IL-2, AKT and BCL-2. We found that IL-2 was elevated in CO-poisoning patients and animal models. Brain tissue damage in CO-poisoning rats was significantly alleviated after NBP treatment. Furthermore, NBP increased the expression of IL-2, AKT and BCL-2 in rat CO-poisoning model. NBP showed neuroprotective action by increasing IL-2, AKT, and BCL-2 expressions.

Si-rhodamine fluorescent probe for monitoring of hypochlorous acid in the brains of mice afflicted with neuroinflammation.

Neuroinflammation leads to a persistent oxidative stress in the brain, and is closely related to the pathology of various neurological disorders. Hypochlorous acid (HClO) is a reactive oxygen species (ROS) that, at high levels, can cause brain tissue damage and neurogenic apoptosis. Herein, we designed and synthesized a silicon-rhodamine (SiR)-based formohydrazide (FH)-containing fluorescent probe, denoted as SiR-FH, for sensing HClO. This probe showed good selectivity, rapid response and high sensitivity. SiR-FH was successfully used to detect endogenous and exogenous HClO in living cells. Moreover, SiR-FH realized real-time monitoring of change in HClO flux in the brains of mice with LPS-induced neuroinflammation. The probe provides a practical tool for the monitoring of oxidative stress related to neuroinflammation.

Effects of Gundelia tournefortii L. on biochemical parameters, antioxidant activities and DNA damage in a rat model of experimental obesity.

The present study was designed to investigate the effects of Gundelia tournefortii L. plant extract on different tissues in terms of DNA damage, biochemical and antioxidant parameter values in rats with high-calorie diets. With this aim, Wistar albino male rats were divided into 4 groups containing 6 rats each and the study was completed over 12 weeks duration. At the end of the implementation process over the 12 weeks, rats were sacrificed and blood and tissue samples were obtained. Analyses were performed on blood and tissue samples. According to results for DNA damage (8-OHdG), in brain tissue the OG2 group was significantly reduced compared to the NC group. For MDA results in liver tissue, OG1 and OG2 groups were determined to increase by a significant degree compared to the control group, while the OG2 group was also increased significantly compared to the obese group. In terms of the other parameters, comparison between the groups linked to consumption of a high calorie diet (HCD) and administration of Gundelia tournefortii L. in terms of antioxidant activities and serum samples obtained statistically significant results. Gundelia tournefortii L. plant extracts had effects that may be counted as positive on antioxidant parameter activity and were especially identified to improve DNA damage and MDA levels in brain tissues. Additionally, consumption of Gundelia tournefortii L. plant extract in the diet may have antiobesity effects; thus, it should be evaluated for use as an effective weight-loss method and as a new therapeutic agent targeting obesity.

Hydrogen Inhalation Ameliorates Oxidative Stress and Glucose Metabolism Disorder in the Brain of Hindlimb Unloading Rats

Many studies have shown that spaceflight causes oxidative stress and induces brain disorder in astronauts, but the counter measurements are lacking. Increasing evidence demonstrated that hydrogen can act as a therapeutic antioxidant. In this study, rats were treated with or without about 5% hydrogen under hindlimb unloading or normal conditions for 28 d. We assessed rat’s brain function by open-field test, step-down passive avoidance test, the neurotransmitter’s level detected by liquid chromatography with tandem mass spectrometry, and Nissl and hematoxylin–eosin staining analysis. We also assessed the oxidative damage by changes of malondialdehyde level, the ratio of reduced glutathione to oxidized glutathione, and superoxide dismutase and catalase activity. Glucose metabolism disorder was disclosed through glucose metabolomic analysis. The underlying mechanism of the effects of hydrogen was analyzed by mRNA sequencing and detecting mRNA and protein levels. Our data showed that hindlimb unloading caused oxidative damage and glucose metabolism disorder in brain tissues and decreased brain function in rats. Hydrogen inhalation reduced oxidative damage, ameliorated glucose metabolism disorder, and alleviated the dysfunction of rat brain function. Peroxisome-proliferator-activated receptor gamma coactivator 1α and brain-derived neurotrophic factor, the key regulators of glucose metabolism and brain function, were obviously affected. This research confirms the protective effect of hydrogen inhalation on declining brain function under hindlimb unloading conditions and discloses the underlying mechanism, which provides a potential strategy for astronauts’ health.

MR Neuroimaging Findings in Adult Diabetic Patients- Two Case Reports

Diabetes Mellitus (DM) can affect any part of the central and peripheral nervous systems. Significant variations in glucose levels are often symptomatic. Hypoglycaemia as well as hyperglycaemia can present a wide variety of clinical symptoms. Imaging helps by suggesting the correct diagnosis and ensuring early treatment. We hereby present two cases, one of hypoglycaemic encephalopathy and a case of diabetic striatopathy. A 40-year-old female with a 25-year-old history of type 2 diabetes was brought into the emergency room in an unresponsive state since afternoon. The blood glucose was 28 mg/dL, and immediate administration of D 25%x2 stat was done. MRI revealed hyperintensities in the bilateral hippocampi and in the cortex of the bilateral high parietal region on T2WI/FLAIR. Despite intensive medical treatment the patient’s neurologic condition didn’t improve, due to irreversible brain tissue damage, and the patient ultimately died. A 63-year-old male was brought by relatives to causality with complaints of involuntary movements of the right-side of the body since three months, but symptoms have exaggerated since three days. Newly diagnosed DM since three months was on medication T.Metformin 500 mg BD. MRI revealed T1 hyperintensities in posterior half of left putamen. Patient was put on Inj. haloperidol 0.5 mg SOS, T.Aspirin 150 mg OD, T.Atorva 20 mg HS, T.sodium valproate 200 mg BD, T.tetrabenazine 25 mg BD and T.Serenace 0.5 mg BD and patient had improved symptomatically after 15 days of treatment. Imaging can play a crucial role in diagnosis and guide treatment and markedly influence the prognosis of patient.

Cognitive Impairment in Children with BetaThalassaemia Major at a Tertiary Care Centre, Rajasthan, India: A Cross-sectional Study

Introduction: Thalassaemia is one of the most common genetic disorders. Iron overload due to repeated blood transfusions and chelating therapy leads to oxidative stress and possible irreversible brain tissue damage, causing cognitive impairment in these children. Aim: To study cognitive impairment in children with beta thalassaemia major in a tertiary care centre in Bikaner, Rajasthan, India. Materials and Methods: This was a hospital-based crosssectional observational study conducted in the Department of Paediatrics, Sardar Patel Medical College, Bikaner, Rajasthan, India from September 2019 to August 2020. Sixty-five children with thalassaemia and 65 children without thalassaemia (as controls) were recruited and assessed using modified MiniMental State Examination (MMSE) for cognitive impairment. Results: Majority of children belonged to age group 6-11 years (67.7% in cases and 68.8% in controls). The mean MMSE scores were significantly lower among children with thalassaemia (26.82±6.45) compared to the controls (29.08±5.71). There was a significantly higher prevalence of cognitive dysfunction in thalassaemia children (72.3%) as compared to controls (33.8%). Children who were compliant with chelation medications (n=30) were found to have a lesser prevalence of cognitive dysfunction (60%) than those who were not compliant (n=35) with medications (82.86%) (p-value=0.013). Among cases, the mean ferritin levels were higher in children with cognitive dysfunction (3399.00±1489.18) compared to those with normal cognitive function (2412.38±1117.26) (p-value=0.046). There was moderate positive correlation between thalassaemia child’s Body Mass Index (BMI) and modified MMSE score. Conclusion: This study highlights the higher prevalence of cognitive impairment in children with thalassaemia (72.3%). The key contributing factors were- lack of compliance to chelation therapy, higher serum ferritin levels and low BMI.

Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury.

After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury (sub-acute phase), genome-wide transcriptomic data showed that interleukin 17A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17A may be a promising therapeutic target for traumatic brain injury.

Primary central nervous system CD20-negative diffuse large B-cell lymphoma: a case report

BackgroundCD20-negative diffuse large B-cell lymphoma is a very rare and heterogeneous invasive cancer characterized by chemical resistance and poor prognosis. Primary CD20-negative diffuse large B-cell lymphoma of the central nervous system is even rarer, presenting great challenges in pathological diagnosis and clinical treatment.Case presentationWe report a case of primary CD20-negative diffuse large B-cell lymphoma of the CNS in a 54-year-old woman admitted to the hospital with a headache lasting more than 10 days. CT and MRI scans showed right temporal lobe lymphoma. Microscopically, large infiltrating lymphoid cells that induced brain tissue damage were observed. Immunohistochemistry showed that the tumor cells were CD79a+, PAX-5+, MUM1+, and CD20-. The patient was diagnosed with lymphoma and transferred to an oncology hospital for chemotherapy. However, because the disease progressed rapidly, the patient died only after two rounds of chemotherapy.ConclusionsTo the best of our knowledge, this is one of the first reported cases of unclassifiable CD20-negative diffuse large B-cell lymphoma located in the CNS. This case report aims to deepen the understanding of clinicopathological features of this type of lymphoma and expand the scope of this disease.

PRUNETIN ATTENUATES D-GALACTOSE-INDUCED BRAIN AGING VIA INHIBITING AMYLOID-Β AND TAU PROTEIN AGGREGATION

The objective of this investigation was to assess the effect of prunetin in D-galactose-induced brain aging in rats and its regulating mechanisms. D-galactose (200 mg kg-1 body wt.) was given orally daily for 45 days to accelerate aging, and prunetin (10, 20,40, and 80 µg kg-1 body wt. respectively) was administered orally. The anti-oxidant and anti-brain aging activities of prunetin in serum were measured by the estimation of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) levels and brain tissues were measured by western blot analysis and histopathological studies. Prunetin therapy decreases elevated levels of glucose, C-reactive protein, cholesterol, and triglyceride levels in the D-galactose-induced rats. D-galactose suppresses the levels of superoxide dismutase, glutathione peroxidase, catalase and total antioxidant capacity in rats; these levels were elevated by treating with prunetin. Malondialdehyde levels were elevated in D-galactose-induced rats. Prunetin significantly decreases the malondialdehyde levels in rat brain tissue. Prunetin decreases mitochondrial dysfunction induced by D-galactose, by improving the activities of Na+K+-ATPase and acetylcholinesterase enzyme activity. Western blot analysis results showed that the degree of brain tissue damage was significantly reduced by prunetin. The results of our study indicated that prunetin treatment reduced oxidative stress by exerting a protective effect against D-galactose-induced aging in rats, by significantly decreasing amyloid - β and tau protein levels in the brain tissue. Prunetin exhibits anti-oxidant activity by increasing anti-oxidant enzymes.

Astrocyte-derived exosome-transported GJA1-20k attenuates traumatic brain injury in rats.

Astrocyte-derived exosome-transported GJA1-20k attenuates traumatic brain injury in rats.

Identification of ligustrazine-based analogs of piperlongumine as potential anti-ischemic stroke agents

Piper longum has a specific aroma and spicy taste. In addition to edible value, current studies have shown that piper longum also has pharmacological activities such as anti-platelet aggregation, anti-inflammation, anti-cancer, anti-diabetes and anti-depression. Piperlongumine is an alkaloid isolated from Piper longum. Based on our previous studies, four Piperlongumine analogs were synthesized, and their anti-platelet aggregation activities were evaluated. Among them, compound 8 has the strongest anti-platelet aggregation activity. Therefore, compound 8 was docked with stroke-related protein targets, and it was found that compound 8 had good binding affinity to MRTF-A complex and Bcl-2. Through animal experiments, it was found that compound 8 could significantly improve the pathological damage of brain tissue after ischemia and could increase the expression of MRTF-A and Bcl-2 in cerebral cortex in rats. These results suggest that compound 8 may have a good inhibitory effect on apoptosis and tissue structurel disorders induced by cerebral ischemia-reperfusion, so as to reduce the injury caused by ischemic stroke.

Antioxidant Intervention to Improve Cognition in the Aging Brain: The Example of Hydroxytyrosol and Resveratrol.

Both physiological and pathological aging processes induce brain alterations especially affecting the speed of processing, working memory, conceptual reasoning and executive functions. Many therapeutic approaches to reduce the impact of brain aging on cognitive functioning have been tested; unfortunately, there are no satisfactory results as a single therapy. As aging is partly contributed by free radical reactions, it has been proposed that exogenous antioxidants could have a positive impact on both aging and its associated manifestations. The aim of this report is to provide a summary and a subsequent review of the literature evidence on the role of antioxidants in preventing and improving cognition in the aging brain. Manipulation of endogenous cellular defense mechanisms through nutritional antioxidants or pharmacological compounds represents an innovative approach to therapeutic intervention in diseases causing brain tissue damage, such as neurodegeneration. Coherently with this notion, antioxidants, especially those derived from the Mediterranean diet such as hydroxytyrosol and resveratrol, seem to be able to delay and modulate the cognitive brain aging processes and decrease the occurrence of its effects on the brain. The potential preventive activity of antioxidants should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability, able to bypass the blood-brain barrier limitation, and that are well standardized.

Inflammatory role of microglia in brain injury caused by subarachnoid hemorrhage.

Early brain injury is a series of pathophysiological changes and direct damage of brain tissue within 72 h after subarachnoid hemorrhage before cerebral vasospasm occurs. Early brain injury is a key factor affecting the prognosis of subarachnoid hemorrhage, and its possible pathological mechanisms include oxidative stress, cell apoptosis, autophagy, and immune inflammation. Microglia are important immune cells of the central nervous system. Microglia play a dual role in protection and injury. Microglia are involved in the occurrence of brain edema, the processes of neuronal apoptosis, and the blood-brain barrier disruption after subarachnoid hemorrhage (SAH) through the signaling pathways mediated by receptors such as Toll-like receptor 4 (TLR4), calcium-sensing receptor (CaSR), and triggering receptor expressed on myeloid cells-1 (TREM-1), which secrete pro-inflammatory cytokines such as interleukins and tumor necrosis factor α. Conversely, they exert their anti-inflammatory and protective effects by expressing substances such as neuroglobin and heme oxygenase-1. This article reviews the latest developments in single-cell transcriptomics for microglia in early brain injury after subarachnoid hemorrhage and its inflammatory role.

The potential mechanisms of TBBPA bis(2-hydroxyethyl) ether induced developmental neurotoxicity in juvenile zebrafish (Danio rerio)

TBBPA bis(2-hydroxyethyl) ether (TBBPA-DHEE), one of the main derivatives of TBBPA, has been widely detected in environmental samples and been discovered to be potential neurotoxic. In this study, the juvenile zebrafish were selected as the research subject to explore the neurotoxicity and its mechanism of low-dose TBBPA-DHEE exposure, and to reveal the neurotoxicity susceptibility in different sexes. Behavioral studies revealed that TBBPA-DHEE could significantly reduce the swimming velocity, maximum acceleration and cumulative duration of high-speed mobility, significantly increasing the cumulative duration of low-speed mobility and average social distance. It significantly reduced the contents of ATP, glutamate and Ca2+ in the whole brain. The histopathological study demonstrated that TBBPA-DHEE could cause brain tissue damage in female and male juvenile zebrafish. The comprehensive data analysis indicated that female zebrafish were more susceptible to TBBPA-DHEE exposure than male zebrafish. Transcriptomic analysis showed that TBBPA-DHEE could significantly affect the expressions of behavioral and development-related genes. Furthermore, female and male juvenile zebrafish have different molecular mechanisms of neurotoxicity. For female juvenile zebrafish, the potential mechanism of neurotoxicity could be that it interfered with the feedback regulation of nerves by affecting the related genes expressions in the signaling pathways such as Ca2+ signaling, Wnt signaling and synapses. For male juvenile zebrafish, the potential mechanism of neurotoxicity may be through affecting the expression of related genes in hormones and neuro-related genes. This research could reveal the potential neurotoxicity of TBBPA-DHEE to aquatic organisms, which will be helpful to reveal the health effects of the emerging environmental pollutants.

Effects of the New Thrombolytic Compound LT3001 on Acute Brain Tissue Damage After Focal Embolic Stroke in Rats.

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10mg/kg LT3001 or tPA at 1.5, 3, or 4.5h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke.

Protective effect of Allium atroviolaceum-synthesized SeNPs on aluminum-induced brain damage in mice

Abstract This study evaluated the possible neuroprotective effect of Allium atroviolaceum extract (AaE)-synthesized selenium nanoparticles (SeNPs) on aluminum (Al)-induced neurotoxicity in mice, explaining the likely mechanisms. Mice were divided into five groups: G1, control; G2, AaE group that received AaE (200 mg/kg) for 4 weeks; and groups 3, 4, and 5 received AlCl3 (100 mg/kg) for 3 weeks. After that, G4 received AaE (200 mg/kg), and G5 received SeNPs-AaE (0.5 mg/kg) for another 1 week. Exposure to AlCl3 boosted oxidative damage in brain tissue as evidenced by a reduction in glutathione concentrations and other antioxidant enzymes along with increased lipid peroxidation and nitric oxide levels. There was also a rise in the concentrations of interleukin-1β, TNF-α, and cyclooxygenase-II activities. AlCl3-treated mice showed reduced brain-derived neurotrophic factor (BDNF) and dopamine levels, increased acetylcholinesterase (AChE) activity, and reduced Bcl-2, and Bax, and caspase-3 activities. Treatment with SeNPs-AaE significantly reduced markers of oxidative stress, inflammation, and apoptosis. In addition, in SeNPs-AaE-treated rats, levels of BDNF and dopamine were significantly increased along with a reduction in AChE as compared with the AlCl3 group. Therefore, our results indicate that SeNPs-AaE has a potential neuroprotective effect against Al-mediated neurotoxic effects because of its powerful antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities.

Preliminary verification of the anti-hypoxia mechanism of Gentiana straminea maxim based on UPLC-triple TOF MS/MS and network pharmacology

BackgroundAnoxia is characterized by changes in the morphology, metabolism, and function of tissues and organs due to insufficient oxygen supply or oxygen dysfunction. Gentiana straminea Maxim (G.s Maxim) is a traditional Tibetan medicine. Our previous work found that G.s Maxim mediates resistance to hypoxia, and we found that the ethyl acetate extract had the best effect. Nevertheless, the primary anti-hypoxia components and mechanisms of action remain unclear.MethodsCompounds from the ethyl acetate extraction of G.s Maxim were identified using UPLC-Triple TOF MS/MS. Then Traditional Chinese Medicine Systematic Pharmacology Database was used to filtrate them. Network pharmacology was used to forecast the mechanisms of these compounds. Male specific pathogen-free Sprague Dawley rats were randomly divided into six groups: (1) Control; (2) Model; (3) 228 mg/kg body weight Rhodiola capsules; (4) 6.66 g/kg body weight the G.s Maxim’s ethyl acetate extraction; (5) 3.33 g/kg body weight the G.s Maxim’s ethyl acetate extraction; (6) 1.67 g/kg body weight the G.s Maxim’s ethyl acetate extraction. After administering intragastric ally for 15 consecutive days, an anoxia model was established using a hypobaric oxygen chamber (7000 m, 24 h). Then Histology, enzyme-linked immunosorbent assays, and western blots were performed to determine these compounds’ anti-hypoxic effects and mechanisms. Finally, we performed a molecular docking test to test these compounds using Auto Dock.ResultsEight drug-like compounds in G.s Maxim were confirmed using UPLC-Triple TOF MS/MS and Lipinski’s rule. The tumor necrosis factor (TNF) signaling pathway, the hypoxia-inducible factor 1 (HIF-1) signaling pathway, and the nuclear factor kappa-B (NF-κB) signaling pathway was signaling pathways that G.s Maxim mediated anti-anoxia effects. The critical targets were TNF, Jun proto-oncogene (JUN), tumor protein p53 (TP53), and threonine kinase 1 (AKT1). Animal experiments showed that the ethyl acetate extraction of G.s Maxim ameliorated the hypoxia-induced damage of hippocampal nerve cells in the CA1 region and reversed elevated serum expression of TNF-α, IL-6, and NF-κ B in hypoxic rats. The compound also reduced the expression of HIF-1α and p65 and increased the Bcl-2/Bax ratio in brain tissue. These findings suggest that G.s Maxim significantly protects against brain tissue damage in hypoxic rats by suppressing hypoxia-induced apoptosis and inflammation. Ccorosolic acid, oleanolic acid, and ursolic acid had a strong affinity with core targets.ConclusionsThe ethyl acetate extraction of G.s Maxim mediates anti-hypoxic effects, possibly related to inhibiting apoptosis and inflammatory responses through the HIF-1/NF-κB pathway. The primary active components might be corosolic, oleanolic, and ursolic acids.