This service exclusively searches for literature that cites resources. Please be aware that the total number of searchable documents is limited to those containing RRIDs and does not include all open-access literature.
Inhibition of the early intracellular event that triggers neurodegenerative cascades and reversal of neuronal cell death are essential for effective treatment of Alzheimer's disease (AD). In this study, a novel therapeutic for AD, a transducible humanin with an extended caspase-3 cleavage sequence (tHN-C3), was developed and showed multiple mechanisms of therapeutic action. These included targeted delivery of anti-apoptotic protein humanin through the blood-brain barrier (BBB) to neuronal cells, specific inhibition of caspase-3 activation to inhibit the early triggering of AD progression, and delivery of humanin into the cytoplasm of neuronal cells undergoing apoptosis where it exerts its anti-apoptotic functions effectively. The tHN-C3 prevented neuronal cell death induced by H2O2, or soluble Aβ42, via Bax binding. In animal models of AD induced by amyloid beta, in Tg2576 mice, and in the rat middle cerebral artery occlusion model of stroke, tHN-C3 effectively prevented neuronal cell death, inflammatory cell infiltration into the brain, and improved cognitive memory. The therapeutic effectiveness of tHN-C3 was comparable to that of Aricept, a clinically approved drug for AD treatment. Therefore, tHN-C3 may be a new remedy with multiple therapeutic functions targeting the early and late stages of neurodegeneration in AD and other brain injuries.
Recent molecular genetic studies have identified 100s of risk genes for various neurodevelopmental and neuropsychiatric disorders. As the number of risk genes increases, it is becoming clear that different mutations of a single gene could cause different types of disorders. One of the best examples of such a gene is SHANK3, which encodes a core scaffold protein of the neuronal excitatory post-synapse. Deletions, duplications, and point mutations of SHANK3 are associated with autism spectrum disorders, intellectual disability, schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Nevertheless, how the different mutations of SHANK3 can lead to such phenotypic diversity remains largely unknown. In this study, we investigated whether Shank3 could form protein complexes in a brain region-specific manner, which might contribute to the heterogeneity of neuronal pathophysiology caused by SHANK3 mutations. To test this, we generated a medial prefrontal cortex (mPFC) Shank3 in vivo interactome consisting of 211 proteins, and compared this protein list with a Shank3 interactome previously generated from mixed hippocampal and striatal (HP+STR) tissues. Unexpectedly, we found that only 47 proteins (about 20%) were common between the two interactomes, while 164 and 208 proteins were specifically identified in the mPFC and HP+STR interactomes, respectively. Each of the mPFC- and HP+STR-specific Shank3 interactomes represents a highly interconnected network. Upon comparing the brain region-enriched proteomes, we found that the large difference between the mPFC and HP+STR Shank3 interactomes could not be explained by differential protein expression profiles among the brain regions. Importantly, bioinformatic pathway analysis revealed that the representative biological functions of the mPFC- and HP+STR-specific Shank3 interactomes were different, suggesting that these interactors could mediate the brain region-specific functions of Shank3. Meanwhile, the same analysis on the common Shank3 interactors, including Homer and GKAP/SAPAP proteins, suggested that they could mainly function as scaffolding proteins at the post-synaptic density. Lastly, we found that the mPFC- and HP+STR-specific Shank3 interactomes contained a significant number of proteins associated with neurodevelopmental and neuropsychiatric disorders. These results suggest that Shank3 can form protein complexes in a brain region-specific manner, which might contribute to the pathophysiological and phenotypic diversity of disorders related to SHANK3 mutations.
Variants of the SHANK3 gene, which encodes a core scaffold protein of the postsynaptic density of excitatory synapses, have been causally associated with numerous brain disorders. Shank3 proteins directly bind zinc ions through their C-terminal sterile α motif domain, which enhances the multimerization and synaptic localization of Shank3, to regulate excitatory synaptic strength. However, no studies have explored whether zinc affects the protein interactions of Shank3, which might contribute to the synaptic changes observed after zinc application. To examine this, we first purified Shank3 protein complexes from mouse brain synaptosomal lysates that were incubated with different concentrations of ZnCl2, and analyzed them with mass spectrometry. We used strict criteria to identify 71 proteins that specifically interacted with Shank3 when extra ZnCl2 was added to the lysate. To characterize the zinc-induced Shank3 interactome, we performed various bioinformatic analyses that revealed significant associations of the interactome with subcellular compartments, including mitochondria, and brain disorders, such as bipolar disorder and schizophrenia. Together, our results showing that zinc affected the Shank3 protein interactions of in vitro mouse synaptosomes provided an additional link between zinc and core synaptic proteins that have been implicated in multiple brain disorders.
We determined the functional effect of the herbal preparation, HemoHIM, on the immune system, by examining the immunomodulatory activities of HemoHIM using immunocompromised mice. In this study, to examine the effect on the restoration of immune cells and balance in the immune system, we utilized a cisplatin-induced immunosuppression mouse model. Mice were injected intraperitoneally with cisplatin, an immunosuppressive anticancer, and then received oral doses of 100, 250, and 500 mg/kg of HemoHIM for 14 days. The HemoHIM prevented the cisplatin-induced loss of body and organ weight. In terms of innate immunity, natural killer (NK) cell activity and phagocytosis increased in the HemoHIM group compared to the cisplatin control group. The HemoHIM group also showed a significantly higher expression of Th1-mediated cytokines (interferon gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α)) and inhibited the production of Th2-mediated cytokine interleukin-4 (IL-4) compared to cisplatin control group. These findings indicate that HemoHIM enhances immune activity by modulating immune cell activity and cytokine secretion in immune-suppressed mice.
Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.
The corneal fibrotic responses to corneal damage often lead to severe corneal opacification thereby resulting in severe visual impairment or even blindness. The persistence of corneal opacity depends heavily on the activity of corneal myofibroblast. Myofibroblasts are opaque and synthesize a disorganized extracellular matrix (ECM) and thus promoting opacification. Cluster of differentiation 147 (CD147), a member of the immunoglobulin superfamily, is known to play important roles in the differentiation process from fibroblast to myofibroblast in damaged cornea and may therefore be an effective target for treatment of corneal opacity. Here, we examined the therapeutic efficacy of novel CD147 inhibiting verbenone derivative SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) on corneal fibrosis. Topical SP-8356 significantly reduced corneal haze and fibrosis in the alkali-burned cornea. In detail, SP-8356 inhibited both alpha-smooth muscle actin (α-SMA) expressing myofibroblast and its ECM-related products, such as matrix-metalloproteinase-9 and collagen type III and IV. Similar to SP-8356, topical corticosteroid (prednisolone acetate, PA) also reduced the ECM-related products and opacification. However, prednisolone acetate failed to decrease the population of α-SMA-positive corneal myofibroblast. In conclusion, SP-8356 is capable enough to prevent corneal haze by preventing pathological fibrosis after severe corneal damage. Therefore, SP-8356 could be a potentially promising therapeutic drug for corneal fibrosis.
N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is one of the major causes for neuronal cell death during cerebral ischemic insult. Previously, we reported that the final product of lipid membrane peroxidation 4-hydroxy-2E-nonenal (HNE) synergistically increased NMDA receptor-mediated excitotoxicity (J Neurochem., 2006). In this study, we investigated the mechanism involved in the synergistic neuronal cell death induced by co-treatment with HNE and NMDA. Although neither HNE (1 µM) nor NMDA (2 µM) alone induced the death of cortical neurons, simultaneous treatment of neuronal cells with HNE and NMDA synergistically evoked the death of the cells. However, the synergistic effect on neuronal death was observed only in the presence of calcium. HNE neither increased the cytosolic calcium level ([Ca(2+)]i) nor altered the NMDA-induced intracellular calcium influx. However, HNE together with NMDA elevated the mitochondrial calcium level and depolarized the mitochondrial transmembrane potential. Furthermore, HNE evoked damage of isolated mitochondria at the cytosolic calcium level (200 nM), which is maximally induced by 2 µM NMDA. Consistently, ATP was depleted in neurons when treated with both HNE and NMDA together. Ciclopirox, a potent inhibitor of mitochondrial permeability transition pore opening (Br. J. Pharmacol., 2005), largely prevented the synergistic damage of mitochondria and death of cortical neurons. Therefore, although low concentrations of HNE and NMDA cannot individually induce neuronal cell death, they can evoke the neuronal cell death by synergistically accelerating mitochondrial dysfunction.
During cerebral ischemia, neurons are injured by various mechanisms including excitotoxicity, oxidative stress, and inflammatory responses. Thus, pharmacological manipulation of multiple cytotoxic pathways has been pursued for the treatment of ischemic injury. Cis-hinokiresinol, a naturally occurring phenylpropanoid, was previously reported to possess anti-oxidant, anti-inflammatory and estrogen-like activities. In the present study, we investigated anti-ischemic effects of trans- and cis-hinokiresinols using in vitro as well as in vivo experimental models. The ORAC and DPPH assays showed that two isomers had similar free radical scavenging activities. However, only trans-hinokiresinol significantly decreased neuronal injury in cultured cortical neurons exposed to oxygen-glucose deprivation (75 min) followed by re-oxygenation (9 h). The differential neuroprotective effect could be due to the stereo-specific augmentation of Cu/Zn-SOD activity by trans-hinokiresinol, when compared with cis-hinokiresinol. Similarly, in rats subjected to transient middle cerebral artery occlusion (1.5 h) followed by 24-h reperfusion, pre-ischemic treatment with trans-hinokiresinol, but not with cis-isomer, reduced cerebral infarct volume. Interestingly, however, post-ischemic treatment with both hinokiresinols (2 and 7 h after onset of ischemia) significantly reduced cerebral infarct. When administered after onset of ischemia, trans-hinokiresinol, but not its cis-isomer reduced nitrotyrosine immunoreactivity in ischemic regions. In contrast, both hinokiresinols suppressed neutrophil infiltration and IL-1β release to a similar extent. The observed differential anti-oxidant, but comparable anti-inflammatory, activities may explain the stereo-specific anti-ischemic activities and different therapeutic time windows of the hinokiresinols examined. More detailed delineation of the anti-ischemic mechanism(s) of hinokiresinols may provide a better strategy for development of efficacious regimens for cerebral ischemic stroke.
Platelet-activating factor (PAF), a potent mediator of inflammatory and immune responses, plays various roles in neuronal functions. However, little is known about the role of PAF/platelet-activating factor receptor (PAF-R) in Parkinson's disease. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in significant increases in PAF species in the striatum of wild-type mice. These increases paralleled PAF-R gene expression in wild-type mice. Although nuclear factor kappa B (NF-κB) DNA-binding activity was increased significantly in MPTP-treated wild-type mice, this increase was not significant in PAF-R antagonist ginkgolide B (GB)-treated mice or PAF-R knockout (PAF-R(-/-)) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, significantly ameliorated the dopaminergic deficits induced by MPTP in wild-type mice. MPTP treatment significantly increased oxidative damage, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglial cells, and microglial differentiation of the M1 type in the striatum of wild-type mice. Consistently, PDTC significantly attenuated MPTP-induced behavioral impairments in wild-type mice. However, dopaminergic deficits, oxidative damage, reactive microglial cells, and behavioral impairments induced by MPTP were not significantly observed in GB-treated mice or PAF-R(-/-) mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R(-/-) mice, indicating that NF-κB is a critical target for neurotoxic modulation of PAF-R. We propose for the first time that PAF/PAF-R can mediate dopaminergic degeneration via an NF-κB-dependent signaling process.
Anti-inflammatory therapy has been intensively investigated as a potential strategy for treatment of cerebral stroke. However, despite many positive outcomes reported in animal studies, anti-inflammatory treatments have not proven successful in humans as yet. Although immunomodulatory activity and safety of Cordyceps species (Chinese caterpillar fungi) have been proven in clinical trials and traditional Asian prescriptions for inflammatory diseases, its anti-ischemic effect remains elusive.
Microglia are recognized as residential macrophageal cells in the brain. Activated microglia play a critical role in removal of dead or damaged cells through phagocytosis activity. During phagocytosis, however, microglia should survive under the harmful condition of self-producing ROS and pro-inflammatory mediators. TGF-β has been known as a classic anti-inflammatory cytokine and controls both initiation and resolution of inflammation by counter-acting inflammatory cytokines. In the present study, to understand the self-protective mechanism, we studied time-dependent change of TNF-α and TGF-β production in microglia phagocytizing opsonized-beads (i.e., polystyrene microspheres). We found that microglia phagocytized opsonized-bead in a time-dependent manner and simultaneously produced both TNF-α and TGF-β. However, while TNF-α production gradually decreased after 6 h, TGF-β production remained at increased level. Microglial cells pre-treated with lipopolysaccharides (a strong immunostimulant, LPS) synergistically increased the production of TNF-α and TGF-β both. However, LPS-pretreated microglia produced TNF-α in a more sustained manner and became more vulnerable, probably due to the marked and sustained production of TNF-α and reduced TGF-β. Intracellular oxidative stress appears to change in parallel with the microglial production of TNF-α. These results indicate TGF-β contributes for the survival of phagocytizing microglia through autocrine suppression of TNF-α production and oxidative stress.
Previously, we reported that glucose-deprived astrocytes are more vulnerable to the cytotoxicity of peroxynitrite, the reaction product of nitric oxide and superoxide anion. The augmented vulnerability of glucose-deprived astrocytes to peroxynitrite cytotoxicity was dependent on their proliferation rate. Inhibition of cell cycle progression has been shown to inhibit the apoptotic cell death occurring in cerebral ischemia-reperfusion. In the present study, we demonstrate that the increased death of glucose-deprived astrocytes by peroxynitrte was largely blocked by the cell cycle phase G2/M transition blocker etoposide. However, the cytoprotective effect of etoposide was not associated with its inhibition of cell cycle progression. Instead, etoposide effectively scavenged peroxynitrite. However, etoposide did not scavenge individual nitric oxide and superoxide anion and it did not prevent the hydrogen peroxide-induced cytotoxicity. The present results indicate that etoposide prevents the toxicity of peroxynitrite in astrocytes by directly scavenging peroxynitrite, not by inhibiting cell cycle progression.
Liver cancer is a common tumor and currently the second leading cause of cancer-related mortality globally. Liver cancer is highly related to inflammation as more than 90% of liver cancer arises in the context of hepatic inflammation, such as hepatitis B virus and hepatitis C virus infection. Despite significant improvements in the therapeutic modalities for liver cancer, patient prognosis is not satisfactory due to the limited efficacy of current drug therapies in anti-metastatic activity. Therefore, developing new effective anti-cancer agents with anti-metastatic activity is important for the treatment of liver cancer. In this study, SP-8356, a verbenone derivative with anti-inflammatory activity, was investigated for its effect on the growth and migration of liver cancer cells. Our findings demonstrated that SP-8356 inhibits the proliferation of liver cancer cells by inducing apoptosis and suppressing the mobility and invasion ability of liver cancer cells. Functional studies revealed that SP-8356 inhibits the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways, which are related to cell proliferation and metastasis, resulting in the downregulation of metastasis-related genes. Moreover, using an orthotopic liver cancer model, tumor growth was significantly decreased following treatment with SP-8356. Thus, this study suggests that SP-8356 may be a potential agent for the treatment of liver cancer with multimodal regulation.
HemoHIM is a medicinal herbal preparation of Angelica gigas Nakai (Apiaceae), Cnidium officinale Makino (Umbelliferae), and Paeonia lactiflora Pallas (Paeoniaceae) designed for immune regulation. In the present study, the memory-enhancing effects of a standardized extract (HemoHIM) on scopolamine-induced memory impairment in a murine model was investigated. To induce amnesia, scopolamine (1 mg/kg) was intraperitoneally (i.p.) injected into mice 30 min before the start of behavioral tests. The Y-maze, novel object recognition test (NORT), and passive avoidance task (PAT) were used to evoke memory functions. HemoHIM significantly improved scopolamine-induced memory impairment in ICR mice, which was evidenced by an improvement of spontaneous alternation in the Y-maze, recognition index in NORT, and latency time in PAT. To elucidate the possible mechanism, the cholinergic activity and mRNA levels of choline acetyltransferase (ChAT), muscarinic acetylcholine receptor (mAchR), brain-derived neurotrophic factor (BDNF), and cAMP response element-binding protein (CREB) were measured using reverse transcription (RT-PCR) and western blot analyses, respectively. HemoHIM treatment attenuated the scopolamine-induced hyperactivation of acetylcholinesterase (AchE) activity. In addition, ChAT, mAchR, and CREB mRNA levels were increased in the hippocampus compared with the scopolamine group. Furthermore, HemoHIM treatment resulted in elevated BDNF protein expression. These results indicate that HemoHIM may exert antiamnesic activity by increasing Ach and inhibiting AchE in the hippocampus. In addition, HemoHIM has therapeutic potential by upregulating ChAT, mAchR, and BDNF, which is apparently mediated by activation of the CREB and ERK signaling pathways.
The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo.
Synthetic vascular smooth muscle cells (VSMCs) play important roles in atherosclerosis, in-stent restenosis, and transplant vasculopathy. We investigated the synthetic activity of VSMCs in the atherosclerotic carotid artery using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Atherosclerosis was induced in rats by partial ligation of the right carotid artery coupled with an atherogenic diet and vitamin D injections (2 consecutive days, 600,000 IU/day). One month later, rats were imaged by F-18 FDG PET. The atherosclerotic right carotid arteries showed prominent luminal narrowing with neointimal hyperplasia. The regions with neointimal hyperplasia were composed of α-smooth muscle actin-positive cells with decreased expression of smooth muscle myosin heavy chain. Surrogate markers of synthetic VSMCs such as collagen type III, cyclophilin A, and matrix metallopeptidase-9 were increased in neointima region. However, neither macrophages nor neutrophils were observed in regions with neointimal hyperplasia. F-18 FDG PET imaging and autoradiography showed elevated FDG uptake into the atherosclerotic carotid artery. The inner vessel layer showed higher tracer uptake than the outer layer. Consistently, the expression of glucose transporter 1 was highly increased in neointima. The present results indicate that F-18 FDG PET may be a useful tool for evaluating synthetic activities of VSMCs in vascular remodeling disorders.
Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-1β in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-κB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IκB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.
Proper neuronal function requires tight control of gene dosage, and failure of this process underlies the pathogenesis of multiple neuropsychiatric disorders. The SHANK3 gene encoding core scaffolding proteins at glutamatergic postsynapse is a typical dosage-sensitive gene, both deletions and duplications of which are associated with Phelan-McDermid syndrome, autism spectrum disorders, bipolar disorder, intellectual disability, or schizophrenia. However, the regulatory mechanism of SHANK3 expression in neurons itself is poorly understood.
Welcome to the FDI Lab - SciCrunch.org Resources search. From here you can search through a compilation of resources used by FDI Lab - SciCrunch.org and see how data is organized within our community.
You are currently on the Community Resources tab looking through categories and sources that FDI Lab - SciCrunch.org has compiled. You can navigate through those categories from here or change to a different tab to execute your search through. Each tab gives a different perspective on data.
If you have an account on FDI Lab - SciCrunch.org then you can log in from here to get additional features in FDI Lab - SciCrunch.org such as Collections, Saved Searches, and managing Resources.
Here is the search term that is being executed, you can type in anything you want to search for. Some tips to help searching:
You can save any searches you perform for quick access to later from here.
We recognized your search term and included synonyms and inferred terms along side your term to help get the data you are looking for.
If you are logged into FDI Lab - SciCrunch.org you can add data records to your collections to create custom spreadsheets across multiple sources of data.
Here are the facets that you can filter your papers by.
From here we'll present any options for the literature, such as exporting your current results.
If you have any further questions please check out our FAQs Page to ask questions and see our tutorials. Click this button to view this tutorial again.
Year:
Count: