Artesunate attenuates traumatic brain injury-induced impairments in rats

AbstractBackgroundBlood–brain barrier (BBB) dysfunction and neuroinflammation induced by traumatic brain injuries (TBIs) cause a succession of secondary brain damage events and finally lead to a massive and progressive cerebral neuronal destruction. Artesunate, a semisynthetic artemisinin derivative, is a potential candidate for the management of cerebral damage induced by TBI due to its protective function to BBB and cerebral neurons.MethodsTo demonstrate the effect of artesunate to TBI-induced BBB dysfunction and neural damage, TBI rat model was constructed by cortical impact injury. Behavioral experiments were used to estimate the impact of the combined treatment on rats. Western blotting was performed to demonstrate the protein levels in the brain tissues of rats. Quantitative real-time PCRs were utilized to investigate the alteration in the expression of various RNA levels. The chemokine levels were estimated by ELISA.ResultsArtesunate treatment attenuated the impact caused by TBI on rat brain and improved the long-term neurological recover. Artesunate treatment protected the integrity of BBB and inhibited neuroinflammation. Artesunate treatment promoted the phosphorylation of Akt and inhibited the phosphorylation of glycogen synthase kinase (GSK)-3β in TBI rat model.ConclusionArtesunate protected rats from TBI-induced impairments of BBB and improved longer-term neurological outcomes.

Download Full-text

Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3β and β-catenin

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145712001010 ◽

2013 ◽

Vol 16 (5) ◽

pp. 945-955 ◽

Cited By ~ 13

Author(s):

Xinguo Ren ◽

Hooriyah S. Rizavi ◽

Mansoor A. Khan ◽

Yogesh Dwivedi ◽

Ghanshyam N. Pandey

Keyword(s):

Protein Expression ◽

Glycogen Synthase ◽

Wnt Signalling ◽

Signalling Pathway ◽

Glycogen Synthase Kinase ◽

Mrna Levels ◽

Protein Levels ◽

Wnt Signalling Pathway ◽

Gsk 3Β ◽

Teenage Suicide

Abstract Glycogen synthase kinase (GSK)-3β and β-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3β and β-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3β and β-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3β protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3β-ser9 were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3β mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of β-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in β-catenin and pGSK-3β-ser9 in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide.

Download Full-text

Potential involvement of glycogen synthase kinase (GSK)-3β in a rat model of multiple sclerosis: evidenced by lithium treatment

Anatomy & Cell Biology ◽

10.5115/acb.2017.50.1.48 ◽

2017 ◽

Vol 50 (1) ◽

pp. 48 ◽

Cited By ~ 7

Author(s):

Meejung Ahn ◽

Jeongtae Kim ◽

Changnam Park ◽

Jinhee Cho ◽

Youngheun Jee ◽

...

Keyword(s):

Multiple Sclerosis ◽

Rat Model ◽

Glycogen Synthase ◽

Lithium Treatment ◽

Glycogen Synthase Kinase ◽

Gsk 3Β

Download Full-text

ROLE OF GSK-3 IN Wnt/β-CATENIN SIGNALING PATHWAY IN OBESITY

Medical Immunology (Russia) ◽

10.15789/1563-0625-rog-2287 ◽

2021 ◽

Vol 23 (4) ◽

pp. 775-780

Author(s):

A. S. Kulakova ◽

I. A. Snimshchikova ◽

M. O. Plotnikova

Keyword(s):

Serum Level ◽

Wnt Signaling ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Obese Patients ◽

Healthy Individuals ◽

Gsk 3Β ◽

The Impact

The complexity of the adipogenesis mechanism results from the impact of multiple cues, among which an important place is held by the components of the Wnt signaling pathway. The search for potential markers of the development of diseases related to obesity aroused an interest in the study of GSK-3 (glycogen synthase kinase), β-catenin. GSK-3β is an intracellular serine / threonine kinase found in the cytoplasm, nucleus, mitochondria, synthesized in all body tissues and involved in regulating metabolic processes, cell proliferation, apoptosis etc. The first of the discovered functions of GSK-3β was the regulation of glycogen synthesis. Active GSK-3β phosphorylates and thereby inhibits glycogen synthase. As a result of the insulin binding to the cell receptor via inositol-3-phosphate, protein kinase B (Akt1) is activated, which, in turn, phosphorylates and inhibits GSK-3β. In addition, GSK-3β is involved in the regulating glucose metabolism. The most important function of GSK-3β is the inhibition of the β-catenin protein. In a resting cell, GSK-3β in complex with the APC and Axin proteins binds and phosphorylates the β-catenin transcription factor, which leads to its ubiquitination and degradation. When Wnt proteins act on the cell, the Dvl protein is activated, which, by binding to GSK-3β, releases β-catenin, preventing its degradation, however, the role of GSK3α/β in the adipocyte inflammatory response has not yet been fully investigated, therefore it seems promising to study the role of GSK-3 in the Wnt/β-catenin signaling pathway in obesityThe aim of the study was to assess the activity of the components of the Wnt signaling pathway in obese patients by measuring the serum level of GSK-3 and β-catenin. There were enrolled 32 patients with progressive forms of I-III degree obesity in the absence of diabetes mellitus. The concentration of serum GSK-3α, GSK-3β, and β-catenin was measured by enzyme-linked immunoassay. Data are presented as absolute and relative (%) number of patients; arithmetic mean; medians, 1 and 3 quartiles – Ме (Q0.25-Q0.75). Obese patients contained a 7.5-fold increased serum level of GSK-3α (785 (371-1317.5) pg/ml) compared to healthy individuals 105 (102.5-110) pg/ml, (p < 0.001), paralleled with increased amount of GSK-3β, which level in obese patients was 295 (190-695) pg/ml, which is by 18.3% higher than those in healthy individuals 241 (218.75-287.5) pg/ml, p = 0.111. Amount of GSK-3 depending on the degree of obesity tended to increase, most often coupled to decreased β-catenin level which is consistent with the literature data and can be considered as a prognostic criterion for the course of pathological processes in obesity.

Download Full-text

Unspliced XBP1 Counteracts β-catenin to Inhibit Vascular Calcification

Circulation Research ◽

10.1161/circresaha.121.319745 ◽

2021 ◽

Author(s):

Liu Yang ◽

Rongbo Dai ◽

Hao Wu ◽

Zeyu Cai ◽

Nan Xie ◽

...

Keyword(s):

Vascular Calcification ◽

Glycogen Synthase ◽

Vascular Diseases ◽

Proteasomal Degradation ◽

Calcium Deposition ◽

Alizarin Red ◽

Protein Levels ◽

Cardiovascular Morbidity And Mortality ◽

Related Transcription Factor ◽

Gsk 3Β

Background: Vascular calcification is a prevalent complication in chronic kidney disease and contributes to increased cardiovascular morbidity and mortality. XBP1 (X-box binding protein 1), existing as the unspliced (XBP1u) and spliced (XBP1s) forms, is a key component of the endoplasmic reticulum stress involved in vascular diseases. However, whether XBP1u participates in the development of vascular calcification remains unclear. Methods: We aim to investigate the role of XBP1u in vascular calcification.XBP1u protein levels were reduced in high phosphate (Pi)-induced calcified vascular smooth muscle cells (VSMCs), calcified aortas from mice with adenine diet-induced chronic renal failure (CRF) and calcified radial arteries from CRF patients. Results: Inhibition of XBP1u rather than XBP1s upregulated in the expression of the osteogenic markers runt-related transcription factor 2 (Runx2) and msh homeobox2 (Msx2), and exacerbated high Pi-induced VSMC calcification, as verified by calcium deposition and Alizarin red S staining. In contrast, XBP1u overexpression in high Pi-induced VSMCs significantly inhibited osteogenic differentiation and calcification. Consistently, SMC-specific XBP1 deficiency in mice markedly aggravated the adenine diet- and 5/6 nephrectomy-induced vascular calcification compared with that in the control littermates. Further interactome analysis revealed that XBP1u bound directly to β-catenin, a key regulator of vascular calcification, via aa 205-230 in its C-terminal degradation domain. XBP1u interacted with β-catenin to promote its ubiquitin-proteasomal degradation and thus inhibited β-catenin/T-cell factor (TCF)-mediated Runx2 and Msx2 transcription. Knockdown of β-catenin abolished the effect of XBP1u deficiency on VSMC calcification, suggesting a β-catenin-mediated mechanism. Moreover, the degradation of β-catenin promoted by XBP1u was independent of glycogen synthase kinase 3β (GSK-3β)-involved destruction complex. Conclusions: Our study identified XBP1u as a novel endogenous inhibitor of vascular calcification by counteracting β-catenin and promoting its ubiquitin-proteasomal degradation, which represents a new regulatory pathway of β-catenin and a promising target for vascular calcification treatment.

Download Full-text

BIO alleviates inflammation through inhibition of GSK-3β in a rat model of intracerebral hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.4.jns183501 ◽

2020 ◽

Vol 133 (2) ◽

pp. 383-391 ◽

Cited By ~ 2

Author(s):

Sha Zhao ◽

Zhen Liu ◽

Zihan Yu ◽

Xinran Wu ◽

Rui Li ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Western Blotting ◽

Rat Model ◽

Glycogen Synthase ◽

Specific Inhibitor ◽

Microglia Activation ◽

Enzyme Linked Immunosorbent Assay ◽

Optimal Dosage ◽

Autologous Whole Blood ◽

Gsk 3Β

OBJECTIVEInflammation plays a key role in secondary brain damage following intracerebral hemorrhage (ICH). Glycogen synthase kinase–3β (GSK-3β) plays a strong proinflammatory role in many CNS diseases, including stroke. The present study was undertaken to examine the effects of 6-bromoindirubin-3ʹ-oxime (BIO), a specific inhibitor of GSK-3β, on inflammation in ICH rats.METHODSAn ICH rat model was induced by autologous whole-blood injection into the striatum. First, 10, 20, 40, 60, 80, or 100 μg/kg BIO was applied to ICH animals to determine an optimal dosage for producing sufficient GSK-3β inhibition in rat ipsilateral hippocampus by Western blotting. Second, 40 μg/kg BIO was applied to ICH rats for 1, 3, 7, or 14 days, respectively, to determine a suitable intervention time course of BIO by Western blotting analysis on GSK-3β. Third, Western blotting and enzyme-linked immunosorbent assay were used for quantification of inflammation-related factors upstream or downstream of GSK-3β in rat ipsilateral hippocampus. Then, immunohistochemical staining was applied to detect activated microglia and apoptotic cells in rat ipsilateral hippocampus. Last, neurobehavioral tests were performed to assess the sensorimotor impairments in the ICH rats.RESULTSThe results show that BIO 1) blocked GSK-3βTyr216 phosphorylation/activation, thus stabilizing β-catenin, increasing upstream brain-derived neurotrophic factor and downstream heat shock protein 70 levels, and decreasing the levels of nuclear factor–κB p65 and cyclooxygenase 2; 2) decreased the levels of the proinflammatory cytokines tumor necrosis factor–α and interleukin (IL)–1β and IL-6 and elevated the level of antiinflammatory cytokine IL-10; 3) inhibited microglia activation and cell apoptosis; and 4) improved the sensorimotor deficits of ICH rats.CONCLUSIONSBIO posttreatment inhibited microglia activation, prevented inflammation and hippocampal cell death, and ameliorated functional and morphological outcomes in a rat ICH model through inactivation of GSK-3β.

Download Full-text

Potential Synergy between Spores of Metarhizium anisopliae and Plant Secondary Metabolite, 1-Chlorooctadecane for Effective Natural Acaricide Development

Molecules ◽

10.3390/molecules25081900 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1900

Author(s):

Abid Hussain ◽

Ahmed Mohammed AlJabr

Keyword(s):

Metarhizium Anisopliae ◽

Date Palm ◽

Combined Treatment ◽

Synergistic Interaction ◽

Plant Secondary Metabolite ◽

In Vitro Tests ◽

Potential Candidate ◽

Biological Index ◽

Mortality Response ◽

The Impact

Date palm dust mites are important pests severely infesting valuable nutritious fruits (dates) of date palm. In search of an alternative to acaricides, joint action of Metarhizium anisopliae EBCL 02049 spores and 1-Chlorooctadecane was evaluated as a potential candidate for the management of Oligonychus afrasiaticus through natural products. In this regard, in vitro tests were performed to evaluate the interaction of M. anisopliae spores with multiple doses of 1-Chlorooctadecane (0.8, 1.6, 2.4, 3.2, and 4.0 mg/mL). Compatibility bioassay results evidenced from vegetative growth (77.7–84.40 mm), sporulation (5.50–7.30 × 106 spores/mL), and germination (96.70–98.20%), revealed that all the tested doses are compatible (biological index > 82) with the spores of M. anisopliae. The impact of combined treatment of spores with 1-Chlorooctadecane in different proportions (Scheme I, II, III, and IV) compared to their sole application against O. afrasiaticus was evaluated by concentration–mortality response bioassays. Results showed that all the combined treatments revealed high mortality compared to the sole application, which showed relatively slow mortality response over time. Toxicity recorded from Scheme IV combinations (80% 1-Chlorooctadecane: 20% Spores), exhibited strong synergistic interaction (joint toxicity = 713). Furthermore, potent interactions have overcome the host antioxidant defense at the final stage of infection by tremendously reducing catalase, and superoxide dismutase activities. These experiments demonstrated fungal–toxin joint synergistic interaction as a promising date palm dust mite management option.

Download Full-text

Influence of Early Life Lead (Pb) Exposure on α-Synuclein, GSK-3β and Caspase-3 Mediated Tauopathy: Implications on Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205015666180801095925 ◽

2018 ◽

Vol 15 (12) ◽

pp. 1114-1122 ◽

Cited By ~ 7

Author(s):

Syed Waseem Bihaqi ◽

Bothaina Alansi ◽

Anwar M. Masoud ◽

Foqia Mushtaq ◽

Gehad M. Subaiea ◽

...

Keyword(s):

Early Life ◽

Caspase 3 ◽

Glycogen Synthase ◽

Alpha Synuclein ◽

Human Neuroblastoma ◽

Knock Out ◽

Pb Exposure ◽

Gsk 3Β ◽

The Impact

Background: Previously we have shown that developmental exposure to the heavy metal lead (Pb) resulted in latent cognitive impairment, upregulation of biomarkers and pathology associated with both the tau and amyloid pathways, however, the impact on Alpha Synuclein (α-Syn) and its relationship to these pathways and their connection to cognitive performance warrant further elucidation. Objective: The present study determined the impact of developmental Pb exposure on the α-Syn pathways in a mouse model knock-out (KO) for murine tau gene and in differentiated human neuroblastoma SHSY5Y cell line exposed to a series of Pb concentrations. Methods: Western blot analysis and RT-PCR were used to assess the levels of intermediates in the tau and α-Syn pathways following postnatal Pb exposure on aged mice lacking tau gene and in differentiated SHSY5Y cells on day 3 and day 6 after the Pb exposure had ceased. Result: Early life Pb exposure is accompanied by latent up-regulation in α-Syn in these mice. Furthermore, prior exposure to Pb in-vitro also resulted in an increase in α-Syn, its phosphorylated forms, as well as an increase in glycogen synthase kinase 3β (GSK-3β) and Caspase-3. Conclusion: An environmental agent can act as a latent inducer of both α-Syn and associated kinases that are involved in tau hyperphosphorylation and may allude to the interactive nature of these two neurodegenerative pathways.

Download Full-text

Docosahexaenoic Acid-Rich Fish Oil Supplementation Reduces Kinase Associated with Insulin Resistance in Overweight and Obese Midlife Adults

Nutrients ◽

10.3390/nu12061612 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1612

Author(s):

Rohith N. Thota ◽

Jessica I. Rosato ◽

Tracy L. Burrows ◽

Cintia B. Dias ◽

Kylie A. Abbott ◽

...

Keyword(s):

Insulin Resistance ◽

Fish Oil ◽

Glycogen Synthase ◽

Inverse Correlation ◽

Omega 3 ◽

Post Intervention ◽

Protein Levels ◽

Gsk 3Β ◽

Midlife Adults ◽

Fish Oil Supplementation

Targeting kinases linked to insulin resistance (IR) and inflammation may help in reducing the risk of type 2 diabetes (T2D) and Alzheimer’s disease (AD) in its early stages. This study aimed to determine whether DHA-rich fish oil supplementation reduces glycogen synthase kinase (GSK-3), which is linked to both IR and AD. Baseline and post-intervention plasma samples from 58 adults with abdominal obesity (Age: 51.7 ± 1.7 years, BMI: 31.9 ± 0.8 kg/m2) were analysed for outcome measures. Participants were allocated to 2 g DHA-rich fish oil capsules (860 mg DHA + 120 mg EPA) (n = 31) or placebo capsules (n = 27) per day for 12 weeks. Compared to placebo, DHA-rich fish oil significantly reduced GSK-3β by −2.3 ± 0.3 ng/mL. An inverse correlation (p < 0.05) was found between baseline insulin and IR and their changes following intervention only in participants with C-reactive protein levels higher than 2.4 mg/L. DHA-rich fish oil reduces GSK-3 and IR, suggesting a potential role of long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) in ameliorating AD risk.

Download Full-text

Reduced DNAJC3 Expression Affects Protein Translocation across the ER Membrane and Attenuates the Down-Modulating Effect of the Translocation Inhibitor Cyclotriazadisulfonamide

International Journal of Molecular Sciences ◽

10.3390/ijms23020584 ◽

2022 ◽

Vol 23 (2) ◽

pp. 584

Author(s):

Eva Pauwels ◽

Becky Provinciael ◽

Anita Camps ◽

Enno Hartmann ◽

Kurt Vermeire

Keyword(s):

Protein Translocation ◽

Combined Treatment ◽

Protein Translation ◽

Reporter Protein ◽

Protein Levels ◽

Unfolded Protein ◽

Enhanced Sensitivity ◽

The Unfolded Protein Response ◽

Protein Response ◽

The Impact

One of the reported substrates for the endoplasmic reticulum (ER) translocation inhibitor cyclotriazadisulfonamide (CADA) is DNAJC3, a chaperone of the unfolded protein response during ER stress. In this study, we investigated the impact of altered DNAJC3 protein levels on the inhibitory activity of CADA. By comparing WT DNAJC3 with a CADA-resistant DNAJC3 mutant, we observed the enhanced sensitivity of human CD4, PTK7 and ERLEC1 for CADA when DNAJC3 was expressed at high levels. Combined treatment of CADA with a proteasome inhibitor resulted in synergistic inhibition of protein translocation and in the rescue of a small preprotein fraction, which presumably corresponds to the CADA affected protein fraction that is stalled at the Sec61 translocon. We demonstrate that DNAJC3 enhances the protein translation of a reporter protein that is expressed downstream of the CADA-stalled substrate, suggesting that DNAJC3 promotes the clearance of the clogged translocon. We propose a model in which a reduced DNAJC3 level by CADA slows down the clearance of CADA-stalled substrates. This results in higher residual translocation into the ER lumen due to the longer dwelling time of the temporarily stalled substrates in the translocon. Thus, by directly reducing DNAJC3 protein levels, CADA attenuates its net down-modulating effect on its substrates.

Download Full-text