LightCF-Net: A Lightweight Long-Range Context Fusion Network for Real-Time Polyp Segmentation.

Automatically segmenting polyps from colonoscopy videos is crucial for developing computer-assisted diagnostic systems for colorectal cancer. Existing automatic polyp segmentation methods often struggle to fulfill the real-time demands of clinical applications due to their substantial parameter count and computational load, especially those based on Transformer architectures. To tackle these challenges, a novel lightweight long-range context fusion network, named LightCF-Net, is proposed in this paper. This network attempts to model long-range spatial dependencies while maintaining real-time performance, to better distinguish polyps from background noise and thus improve segmentation accuracy. A novel Fusion Attention Encoder (FAEncoder) is designed in the proposed network, which integrates Large Kernel Attention (LKA) and channel attention mechanisms to extract deep representational features of polyps and unearth long-range dependencies. Furthermore, a newly designed Visual Attention Mamba module (VAM) is added to the skip connections, modeling long-range context dependencies in the encoder-extracted features and reducing background noise interference through the attention mechanism. Finally, a Pyramid Split Attention module (PSA) is used in the bottleneck layer to extract richer multi-scale contextual features. The proposed method was thoroughly evaluated on four renowned polyp segmentation datasets: Kvasir-SEG, CVC-ClinicDB, BKAI-IGH, and ETIS. Experimental findings demonstrate that the proposed method delivers higher segmentation accuracy in less time, consistently outperforming the most advanced lightweight polyp segmentation networks.

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures.

Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HANDs, but how this occurs is not fully understood. We hypothesize that Meth exacerbates HANDs by enhancing gp120-mediated neuroinflammation. To test this hypothesis, we studied the effect of Meth on gp120-induced microglial activation and the resultant production of proinflammatory cytokines in primary rat microglial cultures. Our results show that Meth enhanced gp120-induced microglial activation, as revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression and IL-1ß processing and release, as assayed by immunoblotting and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, increased the levels of iNOS expression and NO production, and increased the levels of cleaved gasderminD (GSDMD-N; an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger. These results suggest that Meth enhances gp120-associated microglial NLRP3 activation and the resultant proinflammatory responses via mitochondria-dependent signaling.

ResDAC-Net: a novel pancreas segmentation model utilizing residual double asymmetric spatial kernels.

The pancreas not only is situated in a complex abdominal background but is also surrounded by other abdominal organs and adipose tissue, resulting in blurred organ boundaries. Accurate segmentation of pancreatic tissue is crucial for computer-aided diagnosis systems, as it can be used for surgical planning, navigation, and assessment of organs. In the light of this, the current paper proposes a novel Residual Double Asymmetric Convolution Network (ResDAC-Net) model. Firstly, newly designed ResDAC blocks are used to highlight pancreatic features. Secondly, the feature fusion between adjacent encoding layers fully utilizes the low-level and deep-level features extracted by the ResDAC blocks. Finally, parallel dilated convolutions are employed to increase the receptive field to capture multiscale spatial information. ResDAC-Net is highly compatible to the existing state-of-the-art models, according to three (out of four) evaluation metrics, including the two main ones used for segmentation performance evaluation (i.e., DSC and Jaccard index).

ASD-Net: a novel U-Net based asymmetric spatial-channel convolution network for precise kidney and kidney tumor image segmentation.

Early intervention in tumors can greatly improve human survival rates. With the development of deep learning technology, automatic image segmentation has taken a prominent role in the field of medical image analysis. Manually segmenting kidneys on CT images is a tedious task, and due to the diversity of these images and varying technical skills of professionals, segmentation results can be inconsistent. To address this problem, a novel ASD-Net network is proposed in this paper for kidney and kidney tumor segmentation tasks. First, the proposed network employs newly designed Adaptive Spatial-channel Convolution Optimization (ASCO) blocks to capture anisotropic information in the images. Then, other newly designed blocks, i.e., Dense Dilated Enhancement Convolution (DDEC) blocks, are utilized to enhance feature propagation and reuse it across the network, thereby improving its segmentation accuracy. To allow the network to segment complex and small kidney tumors more effectively, the Atrous Spatial Pyramid Pooling (ASPP) module is incorporated in its middle layer. With its generalized pyramid feature, this module enables the network to better capture and understand context information at various scales within the images. In addition to this, the concurrent spatial and channel squeeze & excitation (scSE) attention mechanism is adopted to better comprehend and manage context information in the images. Additional encoding layers are also added to the base (U-Net) and connected to the original encoding layer through skip connections. The resultant enhanced U-Net structure allows for better extraction and merging of high-level and low-level features, further boosting the network's ability to restore segmentation details. In addition, the combined Binary Cross Entropy (BCE)-Dice loss is utilized as the network's loss function. Experiments, conducted on the KiTS19 dataset, demonstrate that the proposed ASD-Net network outperforms the existing segmentation networks according to all evaluation metrics used, except for recall in the case of kidney tumor segmentation, where it takes the second place after Attention-UNet.

HIV-1 envelope protein gp120 modulation of glutamate effects on cortical neuronal synapses: implications for HIV-1-associated neuropathogenesis.

Despite the introduction of combined antiretroviral therapy (cART) HIV-1 virus persists in the brain in a latent or restricted manner and viral proteins, such as gp120, continue to play a significant disease-inciting role. Gp120 is known to interact with N-methyl-D-aspartate (NMDA) receptors (NMDARs) resulting in neuronal injury. Glutamate is the main excitatory neurotransmitter in the brain and plays an important role in cognitive function and dysregulation of excitatory synaptic transmission impairs neurocognition. It is our hypothesis that gp120 may alter synaptic function via modulating glutamate function from a physiological molecule to a pathophysiological substance. To test this hypothesis, we studied the modulatory effects of gp120 and glutamate on NMDAR-mediated spontaneous excitatory postsynaptic current (sEPSCNMDAR) and dynamic dendritic spine changes in rat cortical neuronal cultures. Our results revealed that gp120 and glutamate each, at low concentrations, had no significant effects on sEPSCNMDAR and dendritic spines, but increased sEPSCNMDAR frequency, decreased numbers of dendritic spines when tested in combination. The observed effects were blocked by either a CXCR4 blocker or an NMDAR antagonist, indicating the involvements of chemokine receptor CXCR4 and NMDARs in gp120 modulation of glutamate effects. These results may imply a potential mechanism for HIV-1-associated neuropathogenesis in the cART era.

The Impact of COVID-19 on People Living with HIV-1 and HIV-1-Associated Neurological Complications.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, a fatal respiratory illness. The associated risk factors for COVID-19 are old age and medical comorbidities. In the current combined antiretroviral therapy (cART) era, a significant portion of people living with HIV-1 (PLWH) with controlled viremia is older and with comorbidities, making these people vulnerable to SARS-CoV-2 infection and COVID-19-associated severe outcomes. Additionally, SARS-CoV-2 is neurotropic and causes neurological complications, resulting in a health burden and an adverse impact on PLWH and exacerbating HIV-1-associated neurocognitive disorder (HAND). The impact of SARS-CoV-2 infection and COVID-19 severity on neuroinflammation, the development of HAND and preexisting HAND is poorly explored. In the present review, we compiled the current knowledge of differences and similarities between SARS-CoV-2 and HIV-1, the conditions of the SARS-CoV-2/COVID-19 and HIV-1/AIDS syndemic and their impact on the central nervous system (CNS). Risk factors of COVID-19 on PLWH and neurological manifestations, inflammatory mechanisms leading to the neurological syndrome, the development of HAND, and its influence on preexisting HAND are also discussed. Finally, we have reviewed the challenges of the present syndemic on the world population, with a particular emphasis on PLWH.

Methamphetamine enhancement of HIV-1 gp120-mediated NLRP3 inflammasome activation and resultant proinflammatory responses in rat microglial cultures.

Background: Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms under HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in the HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HAND. How Meth exacerbates HAND is not fully understood. This study was to test the hypothesis that Meth exacerbates HAND by enhancing gp120-mediated proinflammatory responses in the brain, worsening the pathogenesis of HAND. Methods: Experiments were carried out on primary microglial cultures prepared from neonatal SD rats. The purity of microglia was determined by staining with anti-CD11b. Meth and gp120 were applied to microglial cultures. Microglial activation was revealed by immunostaining and Iba-1 expression. The protein expression levels of Pro-IL-1ß, Il-1ß, Iba-1, iNOS, NLRP3, GSDMD and GSDMD-N were detected by western blotting analyses. The levels of proinflammatory cytokine and NO production in the microglia culture supernatants were assayed by ELISA and Griess reagent systems, respectively. NLRP3 activation was uncovered by fluorescent microscopy images displaying NLRP3 puncta labeled by anti-NLRP3 antibody. NLRP3 co-localization with caspase-1 was labeled with antibodies. One-way ANOVA with post hoc Tukey's multiple comparison tests was employed for statistical analyses. Results: Meth enhanced gp120-induced microglia activation revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression, IL-1ß processing and release assayed by immunoblot and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, elevated levels of iNOS expression and NO production, and enhanced levels of cleaved gasderminD (GSDMD-N, an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger, indicating the involvement of mitochondria in Meth enhancement of NLRP3 inflammasome activation in gp120-primed microglia. Conclusions: These results suggest that Meth enhanced gp120-associated microglial NLRP3 activation and resultant proinflammatory responses via mitochondria-dependent signaling.

NLRP3 inflammasome activation and SARS-CoV-2-mediated hyperinflammation, cytokine storm and neurological syndromes.

Despite the introduction of vaccines and drugs for SARS-CoV-2, the COVID-19 pandemic continues to spread throughout the world. In severe COVID-19 patients, elevated levels of proinflammatory cytokines have been detected in the blood, lung cells, and bronchoalveolar lavage, which is referred to as a cytokine storm, a consequence of overactivation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome and resultant excessive cytokine production. The hyperinflammatory response and cytokine storm cause multiorgan impairment including the central nervous system, in addition to a detriment to the respiratory system. Hyperactive NLRP3 inflammasome, due to dysregulated immune response, is the primary cause of COVID-19 severity. The severity could be enhanced due to viral evolution leading to the emergence of mutated variants of concern, such as delta and omicron. In this review, we elaborate on the inflammatory responses associated with the NLRP3 inflammasome activation in COVID-19 pathogenesis, the mechanisms for the NLRP3 inflammasome activation and pathway involved, cytokine storm, and neurological complications as long-term consequences of SARS-CoV-2 infection. Also discussed is the therapeutic potential of NLRP3 inflammasome inhibitors for the treatment of COVID-19.

Methamphetamine augments HIV-1 gp120 inhibition of synaptic transmission and plasticity in rat hippocampal slices: Implications for methamphetamine exacerbation of HIV-associated neurocognitive disorders.

Methamphetamine (Meth) abuse and human immunodeficiency virus type 1 (HIV-1) infection are two major public health problems worldwide. Being frequently comorbid with HIV-1 infection, Meth abuse exacerbates neurocognitive impairment in HIV-1-infected individuals even in the era of combined antiretroviral therapy. While a large body of research have studied the individual effects of Meth and HIV-1 envelope glycoprotein 120 (gp120) in the brain, far less has focused on their synergistic influence. Moreover, it is well-documented that the hippocampus is the primary site of spatial learning and long-term memory formation. Dysregulation of activity-dependent synaptic transmission and plasticity in the hippocampus is believed to impair neurocognitive function. To uncover the underlying mechanisms for increased incidence and severity of HIV-1-associated neurocognitive disorders (HAND) in HIV-1-infected patients with Meth abuse, we investigated acute individual and combined effects of Meth (20 µM) and gp120 (200 pM) on synaptic transmission and plasticity in the CA1 region of young adult male rat hippocampus, a brain region known to be vulnerable to HIV-1 infection. Our results showed that acute localized application of Meth and gp120 each alone onto the CA1 region reduced short-term dynamics of input-output responses and frequency facilitation, and attenuated long-term potentiation (LTP) induced by either high frequency stimulation or theta burst stimulation. A synergistic augmentation on activity-dependent synaptic plasticity was observed when Meth and gp120 were applied in combination. Paired-pulse facilitation results exhibited an altered facilitation ratio, suggesting a presynaptic site of action. Further studies revealed an involvement of microglia NLRP3 inflammasome activation in Meth augmentation of gp120-mediated attenuation of LTP. Taken together, our results demonstrated Meth augmented gp120 attenuation of LTP in the hippocampus. Since LTP is the accepted experimental analog of learning at the synaptic level, such augmentation may underlie Meth exacerbation of HAND observed clinically.

Minocycline attenuation of rat corpus callosum abnormality mediated by low-dose lipopolysaccharide-induced microglia activation.

BACKGROUND: Microglia are resident innate immune cells in the brain, and activation of these myeloid cells results in secretion of a variety of pro-inflammatory molecules, leading to the development of neurodegenerative disorders. Lipopolysaccharide (LPS) is a widely used experimental stimulant in microglia activation. We have previously shown that LPS produced microglia activation and evoked detectable functional abnormalities in rat corpus callosum (CC) in vitro. Here, we further validated the effects of low-dose LPS-induced microglia activation and resultant white matter abnormality in the CC in an animal model and examined its attenuation by an anti-inflammatory agent minocycline. METHODS: Twenty-four SD rats were divided randomly into three groups and intra-peritoneally injected daily with saline, LPS, and LPS + minocycline, respectively. All animals were subject to MRI tests 6 days post-injection. The animals were then sacrificed to harvest the CC tissues for electrophysiology, western blotting, and immunocytochemistry. One-way ANOVA with Tukey's post-test of all pair of columns was employed statistical analyses. RESULTS: Systemic administration of LPS produced microglial activation in the CC as illustrated by Iba-1 immunofluorescent staining. We observed that a large number of Iba-1-positive microglial cells were hyper-ramified with hypertrophic somata or even amoeba like in the LPS-treated animals, and such changes were significantly reduced by co-administration of minocycline. Electrophysiological recordings of axonal compound action potential (CAP) in the brain slices contained the CC revealed an impairment on the CC functionality as detected by a reduction in CAP magnitude. Such an impairment was supported by a reduction of fast axonal transportation evidenced by ß-amyloid precursor protein accumulation. These alterations were attenuated by minocycline, demonstrating minocycline reduction of microglia-mediated interruption of white matter integrity and function in the CC. CONCLUSIONS: Systemic administration of LPS produced microglia activation in the CC and resultant functional abnormalities that were attenuated by an anti-inflammatory agent minocycline.

Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1ß Production in Microglia.

Methamphetamine (Meth) is an addictive psychostimulant abused worldwide. Ample evidence indicate that chronic abuse of Meth induces neurotoxicity via microglia-associated neuroinflammation and the activated microglia present in both Meth-administered animals and human abusers. The development of anti-neuroinflammation as a therapeutic strategy against Meth dependence promotes research to identify inflammatory pathways that are specifically tied to Meth-induced neurotoxicity. Currently, the exact mechanisms for Meth-induced microglia activation are largely unknown. NLRP3 is a well-studied cytosolic pattern recognition receptor (PRR), which promotes the assembly of the inflammasome in response to the danger-associated molecular patterns (DAMPs). It is our hypothesis that Meth activates NLRP3 inflammasome in microglia and promotes the processing and release of interleukin (IL)-1ß, resulting in neurotoxic activity. To test this hypothesis, we studied the effects of Meth on IL-1ß maturation and release from rat cortical microglial cultures. Incubation of microglia with physiologically relevant concentrations of Meth after lipopolysaccharide (LPS) priming produced an enhancement on IL-1ß maturation and release. Meth treatment potentiated aggregation of inflammasome adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), induced activation of the IL-1ß converting enzyme caspase-1 and produced lysosomal and mitochondrial impairment. Blockade of capase-1 activity, lysosomal cathepsin B activity or mitochondrial ROS production by their specific inhibitors reversed the effects of Meth, demonstrating an involvement of inflammasome in Meth-induced microglia activation. Taken together, our results suggest that Meth triggers microglial inflammasome activation in a manner dependent on both mitochondrial and lysosomal danger-signaling pathways.

Role of microglia in methamphetamine-induced neurotoxicity.

Methamphetamine (Meth) is an addictive psychostimulant widely abused around the world. The chronic use of Meth produces neurotoxicity featured by dopaminergic terminal damage and microgliosis, resulting in serious neurological and behavioral consequences. Ample evidence indicate that Meth causes microglial activation and resultant secretion of pro-inflammatory molecules leading to neural injury. However, the mechanisms underlying Meth-induced microglial activation remain to be determined. In this review, we attempt to address the effects of Meth on human immunodeficiency virus (HIV)-associated microglia activation both in vitro and in-vivo. Meth abuse not only increases HIV transmission but also exacerbates progression of HIV-associated neurocognitive disorders (HAND) through activation of microglia. In addition, the therapeutic potential of anti-inflammatory drugs on ameliorating Meth-induced microglia activation and resultant neuronal injury is discussed.

Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K+ current.

Methamphetamine (Meth) abuse not only increases the risk of human immunodeficiency virus-1 (HIV-1) infection, but exacerbates HIV-1-associated neurocognitive disorders (HAND) as well. The mechanisms underlying the co-morbid effect are not fully understood. Meth and HIV-1 each alone interacts with microglia and microglia express voltage-gated potassium (KV) channel KV1.3. To understand whether KV1.3 functions an intersecting point for Meth and HIV-1, we studied the augment effect of Meth on HIV-1 glycoprotein 120 (gp120)-induced neurotoxic activity in cultured rat microglial cells. While Meth and gp120 each alone at low (subtoxic) concentrations failed to trigger microglial neurotoxic activity, Meth potentiated gp120-induced microglial neurotoxicity when applied in combination. Meth enhances gp120 effect on microglia by enhancing microglial KV1.3 protein expression and KV1.3 current, leading to an increase of neurotoxin production and resultant neuronal injury. Pretreatment of microglia with a specific KV1.3 antagonist 5-(4-Phenoxybutoxy)psoralen (PAP) or a broad spectrum KV channel blocker 4-aminopyridine (4-AP) significantly attenuated Meth/gp120-treated microglial production of neurotoxins and resultant neuronal injury, indicating an involvement of KV1.3 in Meth/gp120-induced microglial neurotoxic activity. Meth/gp120 activated caspase-3 and increased caspase-3/7 activity in microglia and inhibition of caspase-3 by its specific inhibitor significantly decreased microglial production of TNF-α and iNOS and attenuated microglia-associated neurotoxic activity. Moreover, blockage of KV1.3 by specific blockers attenuated Meth/gp120 enhancement of caspase-3/7 activity. Taking together, these results suggest an involvement of microglial KV1.3 in the mediation of Meth/gp120 co-morbid effect on microglial neurotoxic activity via caspase-3 signaling.

Inflammasome in drug abuse.

Drug abuse disorders refer to a set of related negative health implications associated with compulsive drug seeking and use. Because almost all addictive drugs act on the brain, many of them cause neurological impairments after long-term abuse. Neuropathological studies have revealed a widespread impairment of the cellular elements. As the key components to limit the damage of neural cells, CNS immune system is also found affected by these drugs, directly or indirectly. It has been shown that drugs of abuse alter neuroimmune gene expression and signaling. Growing studies on neuroimmune factors further demonstrate their indispensable role in drugs-induced neurotoxicity. As an important proinflammatory intracellular receptor, inflammasome is activated in many neurodegenerative diseases in response to a broad range of damage-associated molecular patterns (DAMPs) signals. In the cases of drug abuse, especially in those with comorbid of HIV infection and sustained pain, inflammasome activation significantly promotes the neuroinflammation-associated toxicities. To understand inflammasome in drug-associated neurotoxic activity, we reviewed the role played by inflammasome in drug abuse-induced microglial neurotoxicity and evaluated the potential of imflammasone as a therapeutic target for drug abuse disorders based on recent development of various selective small-molecular inflammasome inhibitors.

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury.

It is widely accepted that human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) plays an important role in HIV-1-induced neural injury and pathogenesis of HIV-1-associated dementia (HAND). Multiple pathways have been proposed for gp120-induced neurotoxicity, amongst is the activation of N-Methyl-D-Aspartate receptors (NMDARs). It has been shown that gp120 causes neuronal injury or death and gp120 transgenic mice exhibit neurological similarity to that of HAND, all of which can be blocked or attenuated by NMDAR antagonists. Several lines of evidence indicate the subtype and location of activated NMDARs are key determinants of the nature of NMDAR physiology. To examine the subtype and the location of NMDARs affected by gp120, we studied gp120 on subtype NMDAR-mediated EPSCs in the CA1 region of rat hippocampal slices through "blind" whole-cell patch recordings. Our results showed bath application of gp120 increased both NR2A- and NR2B-mediated EPSCs possibly via a presynaptic mechanism, with much stronger effect on NR2B-mediated EPSCs. In contrast, gp120 failed on enhancing AMPA receptor-mediated EPSCs. Ca2+ imaging studies revealed that gp120 potentiated glutamate-induced increase of intracellular Ca2+ concentration in rat hippocampal neuronal cultures which were blocked by a NMDAR antagonist, but not by an AMPA receptor antagonist, indicating gp120 induces Ca2+ influx through NMDARs. Further investigations demonstrated that gp120 increased the EPSCs mediated by extrasynaptic NR2BRs. Taken together, these results demonstrate that gp120 interacts with both NR2A and NR2B subtypes of NMDARs with a predominant action on the extrasynaptic NR2B, implicating a role NR2B may play in HIV-1-associated neuropathology.

Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3.

Brain white matter damage is frequently detected in patients infected with human immunodeficiency virus type 1 (HIV-1). White matter is composed of neuronal axons sheathed by oligodendrocytes (Ols), the myelin-forming cells in central nervous system. Ols are susceptible to HIV-1 viral trans-activator of transcription (Tat) and injury of Ols results in myelin sheath damage. It has been demonstrated that activation of voltage-gated K+ (KV) channels induces cell apoptosis and Ols predominantly express K+ channel KV1.3. It is our hypothesis that Tat injures Ols via activation of KV1.3. To test this hypothesis, we studied the involvement of KV1.3 in Tat-induced Ol/myelin injury both in vitro and ex vivo. Application of Tat to primary rat Ol cultures enhanced whole-cell KV1.3 current recorded under voltage clamp configuration and confirmed by specific KV1.3 antagonists Margatoxin (MgTx) and 5-(4-phenoxybutoxy) psoralen (PAP). The Tat enhancement of KV1.3 current was associated with Tat-induced Ol apoptosis, which was blocked by MgTx and PAP or by siRNA knockdown of KV1.3 gene. The Tat-induced Ol injury was validated in cultured rat brain slices, particularly in corpus callosum and striatum, that incubation of the slices with Tat resulted in myelin damage and reduction of myelin basic protein which were also blocked by aforementioned KV1.3 antagonists. Further studies revealed that Tat interacts with KV1.3 as determined by protein pull-down of recombinant GST-Tat with KV1.3 expressed in rat brains and HEK293 cells. Such protein-protein interaction may alter channel protein phosphorylation, resultant channel activity and consequent Ol/myelin injury. Taken together, these results demonstrate an involvement of KV1.3 in Tat- induced Ol/myelin injury, a potential mechanism for the pathogenesis of HIV-1-associated white matter damage.

dl-3-n-Butylphthalide attenuation of methamphetamine-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

AIMS: Methamphetamine (Meth) abuse causes neural injury in the brain. There are no efficacious therapies available to treat Meth-induce neural injury. The present study intended to test the therapeutic potential of dl-3-n-butylphthalide (NBP), a chemical compound extracted originally from the seeds of Chinese Celery, in the amelioration and prevention of Meth-induced neural injury. MAIN METHODS: Experiments were carried out on SH-SY5Y cells. Neuronal injury and apoptotic cell death were detected by MTT assay and analysis of nuclear morphology. Intracellular reactive oxygen species (ROS) was evaluated by dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay and protein expression levels of the apoptosis-related cleaved caspase-3, bcl2 and Bax were determined by western blotting. KEY FINDINGS: Treatment of SH-SY5Y cells with Meth induced cell injury and apoptosis. NBP attenuated Meth-associated cell injury and apoptosis via blockage of Meth-mediated upregulation of intracellular ROS production and inhibition of Meth-induced decrease of cleaved caspase-3/caspase-3 and Bcl-2/Bax ratios. SIGNIFICANCE: The results presented in this study indicate that NBP may have therapeutic benefits in the treatment of Meth-induced neuronal injury in the central nervous system.

Oligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders.

Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonal myelination is highly regulated by neuronal and astrocytic signals and the maintenance of myelin sheaths is a very complex process. Oligodendrocyte damage can cause axonal demyelination and neuronal injury, leading to neurological disorders. Demyelination in the cerebrum may produce cognitive impairment in a variety of neurological disorders, including human immunodeficiency virus type one (HIV-1)-associated neurocognitive disorders (HAND). Although the combined antiretroviral therapy has markedly reduced the incidence of HIV-1-associated dementia, a severe form of HAND, milder forms of HAND remain prevalent even when the peripheral viral load is well controlled. HAND manifests as a subcortical dementia with damage in the brain white matter (e.g., corpus callosum), which consists of myelinated axonal fibers. How HIV-1 brain infection causes myelin injury and resultant white matter damage is an interesting area of current HIV research. In this review, we tentatively address recent progress on oligodendrocyte dysregulation and HAND pathogenesis.

Platelet-activating factor attenuation of long-term potentiation in rat hippocampal slices via protein tyrosine kinase signaling.

It is well established that HIV-1-infected mononuclear phagocytes release platelet activating factor (PAF) and elevated levels of PAF have been detected in blood and in the cerebrospinal fluid (CSF) of acquired immunodeficiency syndrome (AIDS) patients with HIV-associated neurocognitive disorders (HAND). It is our hypothesis that the elevated levels of PAF alter long-term potentiation (LTP) in the hippocampus, leading to neurocognitive dysfunction. To test this hypothesis, we studied the effects of PAF on LTP in the CA1 region of rat hippocampal slices. Our results showed incubation of hippocampal slices with PAF attenuated LTP. The PAF-mediated attenuation was blocked by ginkgolide B, a PAF receptor antagonist, suggesting PAF attenuation of LTP via PAF receptors. Application of lyso-PAF, an inactive PAF analog, had no apparent effect on LTP. Further investigation revealed an involvement of tyrosine kinase in PAF attenuation of LTP, which was demonstrated by lavendustin A (a specific protein tyrosine kinase inhibitor) blockage of PAF attenuation of LTP. As LTP is widely considered as the cellular and synaptic basis for learning and memory, the attenuation of LTP by PAF may contribute at least in part to the HAND pathogenesis.

[HIV-1gp120 injures neurons by alteration of neuronal expressions of NR2B and PSD-95].

OBJECTIVE: To investigate the mechanisms underlying HIV-1 envelope glycoprotein 120 (gp120)-associated neurotoxicity on rat cortical neuronal cultures. METHODS: Experiments were carried out on primary cortical neuronal cultures prepared from fetal Sprague-Dawley fetal rats. Immunocytochemistry and Western blot techniques were employed to examine the changes of the expressions of N-methyl-D-asparate receptors 2B(NR2B) and postsynaptic density 95 (PSD-95) in cultured neurons in the presence and absence of gp120 in the culture media. Gp120-induced neurotoxicity was determined by MTT assay. RESULTS: MTT assay showed gp120 produced dose-dependent neuronal injury when added to the culture media and the gp120-induced neuronal injury was blocked by memantine, a specific NR2B receptor antagonist. Further studies revealed that gp120 induced neuronal injury by up-regulation of NR2B and down-regulation of PSD-95 expressions in rat cortical neurons. CONCLUSION: These results demonstrated that gp120 injures neurons via an increase of NR2B and a decrease of PSD-95 expressions. The gp120-induced neuronal injury can be blocked by a specific NR2B receptor antagonist, suggesting NR2B may function as a potential target for the development of therapeutic strategies.