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Stroke Jul 2024GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089...
BACKGROUND
GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown.
METHODS
Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65 and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting.
RESULTS
BTB09089 significantly promoted motor outcomes in WT but not in GPR65 mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65 mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65 mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65 mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice.
CONCLUSIONS
Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.
PubMed: 38946544
DOI: 10.1161/STROKEAHA.124.046954 -
Expert Opinion on Therapeutic Targets Jul 2024CLEC10A is a C-type lectin receptor that specifically marks the conventional dendritic cell subsets two and three (cDC2 and DC3). It has a unique recognition profile of... (Review)
Review
INTRODUCTION
CLEC10A is a C-type lectin receptor that specifically marks the conventional dendritic cell subsets two and three (cDC2 and DC3). It has a unique recognition profile of glycan antigens, with terminal N-Acetylgalactosamine residues that are frequently present in the tumor microenvironment. Even though CLEC10A expression allows for precise targeting of cDC2 and DC3 for the treatment of cancer, CLEC10A signaling has also been associated with anti-inflammatory responses that would promote tumor growth.
AREAS COVERED
Here, we review the potential benefits and drawbacks of CLEC10A engagement in the tumor microenvironment. We discuss the CLEC10A-mediated effects in different cell types and incorporate the pleiotropic effects of IL-10, the main anti-inflammatory response upon CLEC10A binding.
EXPERT OPINION
To translate this to a successful CLEC10A-mediated immunotherapy with limited tumor-promoting capacities, finding the right ligand presentation and adjuvant combination will be key.
PubMed: 38946482
DOI: 10.1080/14728222.2024.2374743 -
Progress in Neurobiology Jun 2024Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe...
Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.
PubMed: 38945516
DOI: 10.1016/j.pneurobio.2024.102654 -
International Journal of Biological... Jun 2024Cancer poses a significant threat to human health, and monotherapy frequently fails to achieve optimal therapeutic outcomes. Based on this premise, porphyran (PHP), a...
Cancer poses a significant threat to human health, and monotherapy frequently fails to achieve optimal therapeutic outcomes. Based on this premise, porphyran (PHP), a marine polysaccharide with immunomodulatory function, was used as a framework to coat gold nanorods and construct a novel nanomedicine (PHP-MPBA-GNRs) combining photothermal therapy and immunotherapy. In this design, PHP not only maintained the dispersion stability and photothermal stability of gold nanorods but also could be released under weakly acidic conditions to activate anti-tumor immunity. In vivo studies have shown that PHP-MPBA-GNRs can effectively inhibit tumor cell proliferation and reduce metastasis under near-infrared (NIR) light irradiation. Preliminary mechanistic investigation revealed that PHP-MPBA-GNRs could increase reactive oxygen species (ROS) and induce apoptosis in cancer cells. The PHP in PHP-MPBA-GNRs can also activate dendritic cells and up-regulate the expression of co-stimulatory molecules and antigen-presenting complexes. All biological experiments, including in vivo tests, demonstrated that PHP-MPBA-GNRs achieved a combination of photothermal therapy and immunotherapy for tumors.
PubMed: 38945321
DOI: 10.1016/j.ijbiomac.2024.133460 -
Biomedicine & Pharmacotherapy =... Jun 2024Inflammation and immune responses are intricately intertwined processes crucial for maintaining homeostasis and combating against pathogens. These processes involve...
Inflammation and immune responses are intricately intertwined processes crucial for maintaining homeostasis and combating against pathogens. These processes involve complex signaling pathways, notably the Nuclear Factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) pathways, which play crucial roles. Sulforaphane (SFN), a nutraceutic, has emerged as a potential regulator of NF-κB and MAPK signaling pathways, exhibiting anti-inflammatory properties. However, limited knowledge exists regarding SFN's effects on immune cell modulation. This study aimed to assess the immunomodulatory capacity of SFN pretreatment in human dendritic cells (DCs), followed by exposure to a chronic inflammatory environment induced by lipopolysaccharide. SFN pretreatment was found to inhibit the NF-κB and MAPK signaling pathways, resulting in phenotypic changes in DCs characterized by a slight reduction in the expression of surface markers, as well as a decrease of TNF-α/IL-10 ratio. Additionally, SFN pretreatment enhanced the proliferation of Treg-cells and promoted the production of IL-10 by B-cells before exposure to the chronic inflammatory environment. Furthermore, these changes in DCs were found to be influenced by the inhibition of NF-κB and MAPK pathways (specifically p38 MAPK and JNK), suggesting that these pathways may play a role in the regulation of the differentiation of adaptive immune responses (proliferation of T- and IL-10-producing regulatory-cells), prior to SFN pretreatment. Our findings suggest that SFN pretreatment may induce a regulatory response by inhibiting NF-κB and MAPK signaling pathways in an inflammatory environment. SFN could be considered a promising strategy for utilizing functional foods to protect against inflammation and develop immunoregulatory interventions.
PubMed: 38945082
DOI: 10.1016/j.biopha.2024.117056 -
Neoplasia (New York, N.Y.) Jun 2024
PubMed: 38943994
DOI: 10.1016/j.neo.2024.101018 -
STAR Protocols Jun 2024Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy...
Super-resolution imaging provides unprecedented visualization of sub-cellular structures, but the two main techniques used, single-molecule localization microscopy (SMLM) and stimulated emission depletion (STED), are not easily reconciled. We present a protocol to super-impose nanoscale protein distribution reconstructed with SMLM to sub-cellular morphology obtained in STED. We describe steps for tracking cells on etched coverslips and registering images from two different microscopes with 30-nm accuracy. In this protocol, synaptic proteins are mapped in the dendritic spines of primary neurons. For complete details on the use and execution of this protocol, please refer to Inavalli et al..
PubMed: 38943646
DOI: 10.1016/j.xpro.2024.103160 -
Cell Reports Jun 2024Basal dendrites of layer 5 cortical pyramidal neurons exhibit Na and N-methyl-D-aspartate receptor (NMDAR) regenerative spikes and are uniquely poised to influence...
Basal dendrites of layer 5 cortical pyramidal neurons exhibit Na and N-methyl-D-aspartate receptor (NMDAR) regenerative spikes and are uniquely poised to influence somatic output. Nevertheless, due to technical limitations, how multibranch basal dendritic integration shapes and enables multiplexed barcoding of synaptic streams remains poorly mapped. Here, we combine 3D two-photon holographic transmitter uncaging, whole-cell dynamic clamp, and biophysical modeling to reveal how synchronously activated synapses (distributed and clustered) across multiple basal dendritic branches are multiplexed under quiescent and in vivo-like conditions. While dendritic regenerative Na spikes promote millisecond somatic spike precision, distributed synaptic inputs and NMDAR spikes regulate gain. These concomitantly occurring dendritic nonlinearities enable multiplexed information transfer amid an ongoing noisy background, including under back-propagating voltage resets, by barcoding the axo-somatic spike structure. Our results unveil a multibranch dendritic integration framework in which dendritic nonlinearities are critical for multiplexing different spatial-temporal synaptic input patterns, enabling optimal feature binding.
PubMed: 38943640
DOI: 10.1016/j.celrep.2024.114413 -
Journal of the American Chemical Society Jun 2024Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and...
Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel coli ( ) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.
PubMed: 38943624
DOI: 10.1021/jacs.4c04840 -
The Journal of Comparative Neurology Jul 2024Dendritic spines are sites of synaptic plasticity and their head size correlates with the strength of the corresponding synapse. We recently showed that the distribution...
Dendritic spines are sites of synaptic plasticity and their head size correlates with the strength of the corresponding synapse. We recently showed that the distribution of spine head sizes follows a lognormal-like distribution even after blockage of activity or plasticity induction. As the cytokine tumor necrosis factor (TNF) influences synaptic transmission and constitutive TNF and receptor (TNF-R)-deficiencies cause changes in spine head size distributions, we tested whether these genetic alterations disrupt the lognormality of spine head sizes. Furthermore, we distinguished between spines containing the actin-modulating protein synaptopodin (SP-positive), which is present in large, strong and stable spines and those lacking it (SP-negative). Our analysis revealed that neither TNF-deficiency nor the absence of TNF-R1, TNF-R2 or TNF-R 1 and 2 (TNF-R1/R2) degrades the general lognormal-like, skewed distribution of spine head sizes (all spines, SP-positive spines, SP-negative spines). However, TNF, TNF-R1 and TNF-R2-deficiency affected the width of the lognormal distribution, and TNF-R1/2-deficiency shifted the distribution to the left. Our findings demonstrate the robustness of the lognormal-like, skewed distribution, which is maintained even in the face of genetic manipulations that alter the distribution of spine head sizes. Our observations are in line with homeostatic adaptation mechanisms of neurons regulating the distribution of spines and their head sizes.
Topics: Animals; Dendritic Spines; Mice; Receptors, Tumor Necrosis Factor, Type I; Mice, Knockout; Dentate Gyrus; Tumor Necrosis Factor-alpha; Mice, Inbred C57BL; Receptors, Tumor Necrosis Factor, Type II; Neurons; Male; Microfilament Proteins
PubMed: 38943486
DOI: 10.1002/cne.25645