scholarly journals Genistein Protects Epilepsy-Induced Brain Injury Through Regulating The JAK2/STAT3 and Keap1/Nrf2 Signaling Pathways in The Developing Rats

2021 ◽  
Author(s):  
Qing-peng Hu ◽  
Xiang-yi Huang ◽  
Wei Feng ◽  
Fen-fang Chen ◽  
Hong-xia Yan ◽  
...  
Keyword(s):  
Brain Injury ◽  
Western Blot ◽  
Brain Damage ◽  
Mrna Levels ◽  
Central System ◽  
Activated Microglia ◽  
Tnf Α ◽  
Nrf2 Signaling Pathway ◽  
Genistein Treatment ◽  
Stress Pathway

Abstract Background: Epilepsy is a common chronic neurological disease caused by the over-synchronization of neurons that lead to brain dysfunction. Recurrent seizures or status epilepticus can cause irreversible brain damage. The JAK2-STAT3 signal transduction pathway is stimulated by cytokines and involved in various pathological processes including inflammation, apoptosis and immune regulation in central system diseases. Keap1/Nrf2 is an important anti-oxidative stress pathway, which can reduce the toxic effects of oxygen free radicals and endogenous toxins on neurons. Genistein (Gen) can modulate inflammation and neuronal apoptosis, and may thereby have antiepileptic effects. This study aimed to explore the regulation of Genistein on JAK2/STAT3 and Keap1/Nrf2 signaling pathway and the protective effects on brain injury after epilepsy. Methods: Pentylenetetrazole (PTZ) was used to induce epilepsy in developing rats and Genistein was used for pretreatment of epilepsy. The seizure latency, grade scores and duration of the first generalized tonic-clonic seizure (GTCs) were recorded. Hippocampus tissue was sampled at 24 hours post-epilepsy. Immunofluorescence staining was used to observe the number of mature neurons, activated microglia and astrocytes in the hippocampal CA1 region. Western blot and qRT-PCR were used to determine the protein and mRNA levels of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, Nrf2, HO-1, NQO1, caspase3, Bax and Bcl2 in the hippocampus. Results: Immunofluorescence showed that the number of neurons significantly decreased, and activated microglia and astrocytes significantly increased after epilepsy; Western blot and q-PCR showed that the expressions of p-JAK2, p-STAT3, TNF-α, IL-1β, Keap1, caspase3 and Bax significantly increased, while Nrf2, HO-1, NQO1 and Bcl-2 were significantly reduced after epilepsy. These effects were reversed by Genistein treatment. Moreover, Genistein was found to prolong seizure latency and reduce seizure intensity score and duration of generalized tonic-clonic seizures(GTCs). Conclusions: Genistein can activate the Keap1/Nrf2 antioxidant stress pathway and attenuate the activation of microglia and astrocytes. Genistein also inhibits the JAK2-STAT3 inflammation pathway and expression of apoptotic proteins, and increases the number of surviving neurons, thus having a protective effect on epilepsy-induced brain damage.

scholarly journals Hypoxia Inducible Factor-1α Attenuates Ischemic Brain Damage by Modulating Inflammatory Response and Glial Activity

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1359
Author(s):  
Nashwa Amin ◽  
Shijia Chen ◽  
Qiannan Ren ◽  
Xiaoning Tan ◽  
Benson O. A. Botchway ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Brain Damage ◽  
Hypoxia Inducible Factor ◽  
Mrna Levels ◽  
Endothelin 1 ◽  
Hypoxia Inducible Factor 1 ◽  
I Kappa B Alpha ◽  
Tnf Α

Hypoxia-inducible factor 1 can sufficiently control the progress of neurological symptoms after ischemic stroke owing to their actions associated with its downstream genes. In this study, we evaluated the role of HIF-1α in attenuating brain damage after endothelin-1 injection. Focal cerebral ischemia in mice were induced by endothelin-1 microinjection. Hypoxia-inducible factor 1 activator, dimethyloxalylglycine (DMOG), and HIF-1α inhibitor, acriflavine (ACF), were used to evaluate the hypoxia-inducible factor 1 activity during cerebral ischemia. The expression levels of HIF-1α, glial fibrillary acidic protein (GFAP), interleukin-10 (IL-10), inducible nitric oxide synthase (iNOS), phosphorylated I-kappa-B-alpha/total I-kappa-B-alpha (p-IκBα/IκBα) and nuclear factor kappa B (NF-kB) were assessed. Besides, mRNA levels of IL-10, tumor necrosis factor- alpha (TNF-α), and NF-kB were also analyzed. Results showed a noticeable increase in hypoxia-inducible factor 1 and IL-10 levels in the DMOG group with a decline in iNOS, TNF-α, and NF-kB levels, implying the anti-inflammatory role of hypoxia-inducible factor 1 activator following stroke. These findings were further corroborated by GFAP immunostaining that showed astrocytic activation to be inhibited 12 days post-ischemia, as well as histological and TEM analyses that demonstrated hypoxia-inducible factor 1 induction to alleviate neuronal soma damage and cell death. Based on our study, HIF-1α could be a potential therapeutic target for ischemic stroke.

scholarly journals A study on the protective mechanism of mTOR inhibitor Everolimus on brain injury after epilepsy

2020 ◽  
Author(s):  
Xiang-yi Huang ◽  
Qing-peng Hu ◽  
Ya-yu Zheng ◽  
Rong-rong Hu
Keyword(s):  
Brain Injury ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Brain Damage ◽  
Mtor Inhibitor ◽  
Intraperitoneal Administration ◽  
Microglia Activation ◽  
Protective Mechanism ◽  
Regulation Mechanism ◽  
Mrna Levels

Abstract Background: Epilepsy is a common acute and severe disease in infants and children. Recurrent seizures or status epilepticus can cause irreversible brain damage. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, it may also lead to abnormal neuronal signal transduction under pathological conditions, including that of epilepsy. Everolimus (Eve) is an mammalian target of repamycin (mTOR) inhibitor that may affect neuronal excitability and have a therapeutic effect on epilepsy. Therefore, this study aimed to investigate the protective effect of Everolimus on post-epileptic brain injury and the regulation mechanism of the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway. Intraperitoneal administration of kanic acid (KA) 15mg/kg was used to induce epilepsy in the developing rat and Everolimus (1, 2, 5mg/kg) was injected intraperitoneally 2 hours before KA injection. Cerebral cortex tissue was sampled at 24 hours post-epilepsy.Results: The protein and mRNA levels of PI3K、AKt、mTOR、NF-kB and IL-6 as well as microglia activation significantly increased after KA-induced epilepsy, however these effects were inhibited by Everolimus treatment. Furthermore, pretreatment with Everolimus decreased seizure scores and increased seizure latency. This study demonstrates that mTOR inhibitor.Conclusions: Everolimus can decrease the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway, reduce microglia activation, and attenuate seizure susceptibility and intensity, thus having a protective effect on post-epileptic brain damage.

scholarly journals GPR18 Agonist Resolvin D2 Reduces the Early Brain Injury in A Rat Model of Subarachnoid Hemorrhage by Multi-Mechanisms of Protection

2021 ◽  
Author(s):  
Tongyu Zhang ◽  
Gang Zuo ◽  
Hongqi Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
White Matter ◽  
Western Blot ◽  
Rat Model ◽  
Time Course ◽  
Early Brain Injury ◽  
Brain Regions ◽  
White Matter Injury ◽  
Tnf Α

Abstract Background Early brain injury (EBI) is the early phase of secondary complications resulted in poor prognosis of subarachnoid hemorrhage (SAH). GPR18 is a G protein-coupled receptor which has been reported for neuroprotection in ischemia. In this study, we aimed to use resolvin D2 (RvD2) as an agonist to investigate the roles of GPR18 in different brain regions during EBI. Methods Location and time course of GPR18 after SAH were measured with immunofluorescence and western blot in endovascular perforation rat model. RvD2 was given one hour intranasally post-SAH, and SAH grades, neurobehavior and brain water content tests were performed after 24 hours. TUNEL and DHE staining were measured 24 hours post-SAH in cortex. Immunofluorescence, western blot and immunohistochemistry of proteins related to EBI in different brain regions were also performed. Results We found GPR18 mainly located in meninges, hypothalamus, cortex and white matter. And GPR18 expression increased in meninges and hypothalamus after EBI, however, it decreased in cortex and white matter. RvD2 could improve neurological scores and brain edema. Mast cell degranulation was attenuated, Chymase and Typtase expression decreased after RvD2 administration in meninges. RvD2 attenuated inflammation with increase of POMC, IL-10 and decrease of NPY, TNF-α in hypothalamus. In cortex, RvD2 alleviated oxidative stress and apoptosis, protected blood-brain barrier. RvD2 also ameliorated white matter injury by MBP elevation and APP depression. Conclusions Current results emphasized the importance of GPR18 in the whole brain during EBI. Upregulation of GPR18 with RvD2 may improve neurological functions with multi-mechanisms in different brain regions.

scholarly journals Posttraumatic midazolam administration does not influence brain damage after experimental traumatic brain injury

2021 ◽  
Author(s):  
Anne Sebastiani ◽  
Simone Bender ◽  
Michael K.E. Schäfer ◽  
Serge C. Thal
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Damage ◽  
Inflammatory Marker ◽  
Quantitative Polymerase Chain Reaction ◽  
Experimental Studies ◽  
Experimental Investigations ◽  
Motor Deficits ◽  
Marker Genes ◽  
Mrna Levels

Abstract Background The benzodiazepine midazolam is a γ-aminobutyric acid (GABA)-A receptor agonist frequently used for sedation or stress control in patients suffering from traumatic brain injury (TBI). However, experimental studies on benzodiazepines have reported divergent results, raising concerns about its widespread use in patients. Some studies indicate that benzodiazepine-mediated potentiation of GABAergic neurotransmission is detrimental in brain-injured animals. However, other experimental investigations demonstrate neuroprotective effects, especially in pretreatment paradigms. This study investigated whether single-bolus midazolam administration influences secondary brain damage post-TBI.Methods Two different midazolam dosages (0.5 and 5 mg/kg BW), a combination of midazolam and its competitive antagonist flumazenil, or vehicle solution (NaCl 0.9%) was injected intravenously to mice 24 h after experimental TBI induced by controlled cortical impact. Mice were evaluated for neurological and motor deficits using a 15-point neuroscore and the rotarod test. Histopathological brain damage and mRNA expression of inflammatory marker genes were analyzed using quantitative polymerase chain reaction three days after insult.Results Histological brain damage was not affected by posttraumatic midazolam administration. Midazolam impaired functional recovery, and this effect could not be counteracted by administering the midazolam antagonist flumazenil. An increase in IL-1β mRNA levels due to postinjury application of midazolam was reversible by flumazenil administration. However, other inflammatory parameters were not affected.Conclusions This study merely reports minor effects of a postinjury midazolam application. Further studies focusing on a time-dependent analysis of posttraumatic benzodiazepine administration are required.

scholarly journals Erythropoietin-Derived Peptide Protects Against Acute Lung Injury After Rat Traumatic Brain Injury

2017 ◽  
Vol 41 (5) ◽  
pp. 2037-2044 ◽  
Author(s):  
Yuan Liu ◽  
Junyu Lu ◽  
Xiaoya Wang ◽  
Liu Chen ◽  
Su Liu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Acute Lung Injury ◽  
Brain Injury ◽  
Lung Injury ◽  
Lavage Fluid ◽  
Protective Role ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Tnf Α ◽  
Weight Drop

Background: Traumatic brain injury (TBI) can be complicated by TBI-triggered acute lung injury (ALI), in which inflammation plays a central role. It has been reported that an Erythropoietin-derived peptide (pHBSP) was able to ameliorate TBI; however, its function in TBI-caused ALI has not been reported yet. Methods: In this study, we studied the effect of pHBSP on TBI-caused ALI by using a weight-drop induced TBI model. At 8 h and 24 h post-TBI, pulmonary edema (PE) and bronchoalveolar lavage fluid (BALF) proteins were measured, and haematoxylin and eosin (H&E) staining of lung sections was carried out. At 24 h following TBI, the lungs were harvested for immunofluorescence staining and qRT-PCR analysis. Results: At 8 h and 24 h post-TBI, pHBSP treatment significantly decreased wet/dry ratios, decreased total BALF protein, and attenuated the histological signs of pulmonary injury. At 24 h post-TBI, pHBSP treatment decreased the accumulation of CD68+ macrophages in the lung and reduced the mRNA levels of TNF-α, IL-6, IL-1β and iNOS in the lung. Conclusions: We identified the protective role that pHBSP played in TBI-caused ALI, suggesting that pHBSP is a potent candidate for systemic therapy in TBI patients.

TIPE2 Suppresses Pseudomonas aeruginosa Keratitis by Inhibiting NF-κB Signaling and the Infiltration of Inflammatory Cells

2019 ◽  
Vol 220 (6) ◽  
pp. 1008-1018 ◽  
Author(s):  
Qun Wang ◽  
Li Ma ◽  
Ting Liu ◽  
Cheng Ge ◽  
Qingjun Zhou ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Western Blot ◽  
Ribonucleic Acid ◽  
Inflammatory Cells ◽  
Signaling Molecules ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Mrna Levels ◽  
Corneal Inflammation ◽  
Tnf Α

AbstractBackgroundThe role of tumor necrosis factor α (TNF-α) induced protein 8-like-2 (TIPE2) in Pseudomonas aeruginosa (PA) keratitis was explored.MethodsEight-week-old TIPE2 knockout (TIPE2−/−) C57BL/6 mice and their wild-type (WT) littermates were used. Corneal disease was graded at 1, 2, and 3 days postinfection, and slit lamp, clinical score, histopathology, and immunostaining were performed in the infected corneas. The corneas were harvested, and messenger ribonucleic acid (mRNA) levels of TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) were tested. Enzyme-linked immunosorbent assay (ELISA) determined the protein levels, and nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling molecules were tested by Western blot. In vitro human corneal epithelial cells (HCECs) were used to determine the relationship between TIPE2 and TAK1. The HCECs were treated with TIPE2 short hairpin ribonucleic acid (shRNA) and lipopolysaccharide (LPS) to test the NF-κB signaling molecules by Western blot.ResultsPseudomonas aeruginosa infection induced a decreased expression of TIPE2 in mouse corneas 2 days postinfection. Compared with the control group, TIPE2-deficient mice were susceptible to infection with PA and showed increased corneal inflammation. Reduced NF-κB signaling and inflammatory cell infiltration were required in the TIPE2-mediated immune modulation.ConclusionsTIPE2 promoted host resistance to PA infection by suppressing corneal inflammation via regulating TAK1 signaling negatively and inhibiting the infiltration of inflammatory cells.

scholarly journals Bu-Zhong-Yi-Qi Granule Enhances Colonic Tight Junction Integrity via TLR4/NF-κB/MLCK Signaling Pathway in Ulcerative Colitis Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xiuhong Kang ◽  
Mengdi Jia ◽  
Luqing Zhao ◽  
Shengsheng Zhang
Keyword(s):  
Ulcerative Colitis ◽  
Tight Junction ◽  
Western Blot ◽  
Activity Index ◽  
Damage Index ◽  
Interleukin 10 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Tnf Α

Background. Bu-zhong-yi-qi granule (BZYQ), a sort of Chinese herbal medicine, has exhibited therapeutic effects on ulcerative colitis (UC). However, the mechanism of BZYQ has not been fully clarified. This study was aimed at investigating the effects of BZYQ on UC rats model and at exploring its potential mechanism. Methods. The UC rats were established by enema of trinitrobenzene sulfonic acid (TNBS). The therapeutic effects of BZYQ treatment were evaluated by disease activity index (DAI), colon macroscopic damage index (CMDI) scores, and histological observation. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) were measured by quantitative real time-polymerase chain reaction (qPCR). The expression of tight junction (TJ) proteins, occludin and claudin-1, in the colon was determined by Western blot and immunofluorescence. The expression of toll-like receptors 4 (TLR4), nuclear factor-kappa B (NF-κB), p-NF-κB, myosin light chain kinase (MLCK), MLC, and p-MLC levels in colon was determined by Western blot or qPCR. Results. The results showed that BZYQ could attenuate DAI, CMDI, and histological inflammation. TJ proteins expression was decreased in UC rats, but treatment with BZYQ restored the expression of occludin and claudin-1. In addition, BZYQ administration ameliorated UC-associated increase in the production of TNF-α, IL-1β, and the expression of TLR4, NF-κB, p-NF-κB, MLCK, MLC, and p-MLC, while BZYQ administration increased the production of IL-10. Conclusions. The therapeutic effect of BZYQ on UC is at least partially through regulation of the secretion of some inflammatory cytokines and improvement of TJ integrity via TLR4/NF-κB/MLCK pathway.

scholarly journals Punicalagin Prevents Inflammation in LPS-Induced RAW264.7 Macrophages by Inhibiting FoxO3a/Autophagy Signaling Pathway

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2794 ◽  
Author(s):  
Cao ◽  
Chen ◽  
Ren ◽  
Zhang ◽  
Tan ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Inflammatory Responses ◽  
Raw264.7 Macrophages ◽  
Tnf Α ◽  
Autophagy Inhibition ◽  
Pro Inflammatory Cytokines

Punicalagin, a hydrolysable tannin of pomegranate juice, exhibits multiple biological effects, including inhibiting production of pro-inflammatory cytokines in macrophages. Autophagy, an intracellular self-digestion process, has been recently shown to regulate inflammatory responses. In this study, we investigated the anti-inflammatory potential of punicalagin in lipopolysaccharide (LPS) induced RAW264.7 macrophages and uncovered the underlying mechanisms. Punicalagin significantly attenuated, in a concentration-dependent manner, LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 release at the highest concentration. We found that punicalagin inhibited NF-κB and MAPK activation in LPS-induced RAW264.7 macrophages. Western blot analysis revealed that punicalagin pre-treatment enhanced LC3II, p62 expression, and decreased Beclin1 expression in LPS-induced macrophages. MDC assays were used to determine the autophagic process and the results worked in concert with Western blot analysis. In addition, our observations indicated that LPS-induced releases of NO, TNF-α, and IL-6 were attenuated by treatment with autophagy inhibitor chloroquine, suggesting that autophagy inhibition participated in anti-inflammatory effect. We also found that punicalagin downregulated FoxO3a expression, resulting in autophagy inhibition. Overall these results suggested that punicalagin played an important role in the attenuation of LPS-induced inflammatory responses in RAW264.7 macrophages and that the mechanisms involved downregulation of the FoxO3a/autophagy signaling pathway.

scholarly journals Impressic Acid Ameliorates Atopic Dermatitis-Like Skin Lesions by Inhibiting ERK1/2-Mediated Phosphorylation of NF-κB and STAT1

2021 ◽  
Vol 22 (5) ◽  
pp. 2334
Author(s):  
Jae Ho Choi ◽  
Gi Ho Lee ◽  
Sun Woo Jin ◽  
Ji Yeon Kim ◽  
Yong Pil Hwang ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Skin Lesions ◽  
Histopathological Analysis ◽  
Mrna Levels ◽  
Chemokine Production ◽  
Dermal Thickness ◽  
Skin Symptoms ◽  
Tnf Α ◽  
Ifn Γ ◽  
In Cells

Impressic acid (IPA), a lupane-type triterpenoid from Acanthopanax koreanum, has many pharmacological activities, including the attenuation of vascular endothelium dysfunction, cartilage destruction, and inflammatory diseases, but its influence on atopic dermatitis (AD)-like skin lesions is unknown. Therefore, we investigated the suppressive effect of IPA on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin symptoms in mice and the underlying mechanisms in cells. IPA attenuated the DNCB-induced increase in the serum concentrations of IgE and thymic stromal lymphopoietin (TSLP), and in the mRNA levels of thymus and activation regulated chemokine(TARC), macrophage derived chemokine (MDC), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in mice. Histopathological analysis showed that IPA reduced the epidermal/dermal thickness and inflammatory and mast cell infiltration of ear tissue. In addition, IPA attenuated the phosphorylation of NF-κB and IκBα, and the degradation of IκBα in ear lesions. Furthermore, IPA treatment suppressed TNF-α/IFN-γ-induced TARC expression by inhibiting the NF-κB activation in cells. Phosphorylation of extracellular signalregulated protein kinase (ERK1/2) and the signal transducer and activator of transcription 1 (STAT1), the upstream signaling proteins, was reduced by IPA treatment in HaCaT cells. In conclusion, IPA ameliorated AD-like skin symptoms by regulating cytokine and chemokine production and so has therapeutic potential for AD-like skin lesions.

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