Nerve Cells Research Articles

Immune profiling of human vestibular schwannoma secretions identifies TNF-α and TWEAK as cytokines with synergistic potential to impair hearing

BackgroundVestibular schwannoma (VS) is an intracranial tumor arising from the Schwann cells of the vestibular nerve and is an important cause of sensorineural hearing loss (SNHL) in humans. The mechanisms underlying this SNHL are incompletely understood and currently, there are no drugs FDA approved specifically for VS. This knowledge gap significantly limits the development of effective treatments aimed at preventing, stabilizing, or reversing VS-induced SNHL.MethodsTo identify effector molecules involved in VS-induced SNHL, we analyzed 47 immune-related factors secreted by tumor tissue in over 50 patients with sporadic VS and studied their correlation with preoperative hearing ability and tumor size. The most promising effector molecules were validated in vivo in an anatomically accurate mouse model of VS, and in vitro with mouse fibroblasts (L929) and auditory cell lines representing pro-sensory precursors of hair cells (UB-OC1) and auditory neuroblasts (US-VOT-N33).ResultsWe demonstrated that VS-induced SNHL was linked to increased secretion of TNF-α, IL-2R, CD163, eotaxin, and HGF, while larger tumor size was associated with higher levels of TNF-α, TNF-R2, IL-1α, IFN-α, MIP-1β, and IL-21 secretion. We identified heterogeneity among VS tumors in their capacity to secrete TNF-α. Tumors with high levels of TNF-α secretion released cytokines and chemokines that significantly correlated with poor hearing (TWEAK and eotaxin) or better hearing (LIF, GRO-α, MIP-1α, MIP-3α, and IL-1α). Among these, TWEAK was notably abundant, with levels exceeding those in normal nerve tissue, elevated in patients with non-serviceable hearing and strongly linked to poor hearing in patients with TNF-α high-secreting tumors. In vivo, we demonstrated that VS-secreted factors reach the inner ear, with elevated TNF-α and TWEAK in the perilymph and blood of tumor-bearing mice with impaired hearing. In vitro, TWEAK amplified TNF-α -mediated cytotoxicity in TNF-α sensitive cells (L929) and auditory cell lines (UB-OC1 and US-VOT-N33) at tumor-secreted concentrations.ConclusionThis study provides compelling evidence that VS-secreted TNF-α and TWEAK act synergistically to drive tumor-induced SNHL. Targeting the TNF-α/TWEAK axis presents a promising new avenue for preventing VS-induced SNHL.

Microscale insight into the proton concentration during electrolytic reaction via an optical microfiber: potential for microcurrent monitoring by a dielectric probe

Local microcurrent monitoring is of great significance for biological and battery systems, yet it poses a formidable challenge. The current measurement techniques rely on electromagnetic materials which inevitably introduce interference to the system under examination. To address this issue, a promising approach based on a dielectric fiber-optic sensor is demonstrated. The microfiber is capable of detecting microcurrent through monitoring the localized proton concentration signal with a pH resolution of 0.0052 pH units. By sensing the refractive index variation surrounding the sensor induced by the interaction between local proton concentration changes and oxidizer-treated microfiber surface through the evanescent field, this sensing mechanism effectively avoids the interference of the electromagnetic material on the performance of the tested system. This sensor exhibits a limit of detection for microcurrent of 1 μA. The sensing region is a microfiber with a diameter of 8.8 μm. It can get invaluable information that cannot be obtained through conventional electrochemical methods. Examples include photocurrent attenuation in photogenerated carrier materials during illumination, electrical activation in nerve cells, and fluctuations in the efficiency of electrical energy generation during battery discharge. This approach provides a powerful complement to electrochemical methods for the elucidation of microscale reaction mechanisms. The information provided by the prepared dielectric fiber-optic sensor will shed more light on proton kinetics and electrochemical and electrobiological mechanisms, which may fill an important gap in the current bioelectricity and battery monitoring methods.

Parkinsons Detection from Gait Time Series Classification Using Modified Metaheuristic Optimized Long Short Term Memory

Neurodegenerative conditions are defined by the progressive deterioration and death of nerve cells in the core neural system. Most neurodegenerative conditions are not curable. While there have been significant improvements and techniques used to treat these diseases early diagnosis continues to play a crucial role in the entire approach. Conditions are often diagnosed only once they start negatively impacting the daily life of those affected. Early detection and timely preventative treatment can help improve patient subjective well-being. This study examines the application of a non-invasive gait analysis technique for the detection of Parkinson’s disease. Publicly available data collected from patients suffering from Parkinson’s along with control groups is utilized and combined with long-short-term neural networks to construct models capable of detecting signs on Parkinson’s disorder. However, because of the significant reliance of models on appropriate parameters selection, metaheuristic algorithms are used to fine tune the selection process, and a modified variation of the strongly founded PSO algorithm was proposed. Several contemporary optimizers are compared based on their ability to optimize model performance. This suggested approach achieved the superior outcomes with an accuracy of 89.92%. The constructed models have been evaluated to determine feature importance using game theory based methods.

Novel histone deacetylase-5 inhibitor T2943 exerts an anti-depressive effect in mice by enhancing GRID1 expression

Histone deacetylase-5 (HDAC5) is implicated in the pathogenesis of depression and the mechanistic pathways underlying the effects of antidepressant medications. We previously identified a novel HDAC5 inhibitor, T2943, with antidepressant properties that promote histone 3 lysine-14 acetylation (H3K14ac) by inhibiting HDAC5 activity. In this study, we identify the core genes promoting transcription and expression following T2943-mediated upregulation of H3K14ac, highlighting Grid1 (GluD1) as a central gene. We used cleavage under targets and tagmentation (CUT&Tag), gene set enrichment analysis, and behavioral tests after GRID1 (glutamate receptor delta-1 subunit) knockdown. Gene ontology and pathway enrichment analysis via CUT&Tag suggested the following mechanism for the antidepressant action of T2943: T2943 inhibits HDAC5 activity to promote H3K14 acetylation. This modification loosens the chromatin structure, allowing transcription factors to bind to the Grid1 promoter region and enhance its transcription and expression. Upregulated GRID1 mediates signal transmission in neural pathways, restores the regenerative ability of hippocampal nerve cells, promotes nerve growth and synaptic formation, increases synapse numbers, and enhances synaptic function. Our findings highlight the therapeutic potential of targeting HDAC5 in depression and clarify the antidepressant mechanism of T2943.

Therapeutic effect of dihydroartemisinin on Alzheimer’s disease model mice with senile macular degeneration

ObjectivesThis study focuses on the preventive and therapeutic effects of Dihydroartemisinin (DHA) on Alzheimer’s disease (AD) model mice and the effects of DHA and donepezil on amyloid β-protein deposition and autophagy in nerve cells.MethodsSix autophagy related targets were selected for molecular docking with DHA to predict the affinity between DHA and the target. The AD mouse model was established and treated with donepezil and DHA, respectively. Morris water maze was used to detect the spatial learning and memory ability of AD mice. Hematoxylin eosin (he) staining was used to observe the structural changes of cerebral cortical neurons and retina, and transmission electron microscope was used to observe the structural changes of mitochondria and synapses. Immunohistochemistry (IHC) and immunofluorescence staining were used to detect the deposition of amyloid beta protein. Western blot was used to detect the expression of apoptosis and autophagy related proteins in the brain tissue of mice in each group.ResultsThe results of molecular docking showed that the selected active compounds had good binding activity with the target. The binding energy between DHA and Aβ, Bcl-2, ATG5, LC3, Caspase3, LAMP1 is −5.7, −7.0, −5.8, −7.2, −6.9 kcal/mol. The water maze test showed that compared with the wild type (WT) group, the spatial memory ability of AD model group mice (5× FAD) was significantly decreased, and the search time (27.62 ± 6.51 s vs. 282.80 ± 17.15 s) and average path (106.30 ± 29.65 cm vs. 993.20 ± 135.80 cm) were significantly prolonged. The application of donepezil and DHA significantly shortened the exploration time and average path (donepezil: 116.10 ± 10.58 s, 529.40 ± 106.00 cm; DHA: 99.71 ± 14.22 s, 373.30 ± 60.97 cm). The path to find the platform in DHA treatment group was shorter than donepezil treatment group (P < 0.05). HE staining showed that the arrangement of nerve cells in 5× FAD mice was disordered, and IHC showed that amyloid β-protein deposition was obvious. DHA and donepezil could improve the damage of cerebral cortex structure and reduce the deposition of extracellular amyloid β-protein in AD mice. Transmission electron microscopy showed that DHA and donepezil could reduce mitochondrial vacuolation and synaptic edema. The above results showed that DHA treatment effect was better than donepezil. Compared with the conventional feeding group, autophagy and apoptosis related proteins B-cell lymphoma-2 (BCL2) and anti-thymocyte globulin (ATG) were significantly down regulated in the 5× FAD group, and the expressions of BCL2 and ATG were increased after treatment with DHA and donepezil.ConclusionsDHA combined with BCL2 and ATG protein, through promoting autophagy protein, can reduce the damage of cerebral cortex structure in AD mice, reduce the deposition of extracellular β-amyloid protein, and then improve the memory ability of AD model mice. DHA treatment is superior to donepezil monotherapy.

Inhibition and Degradation of Amyloid Beta Fibrils by Peptide Inhibitors.

Abnormal amyloid beta (Aβ) aggregation in the form of plaques and its deposition across the human nerve cells are a major hallmark of Alzheimer's disease. Aβ aggregation dynamics and, more importantly, various drugs' effects, either to inhibit the fibril aggregation or to degrade the mature fibrils, have been an area of active research. Large molecule (peptide-based) inhibitors, such as decapeptide (RYYAAFFARR) and pentapeptide (LPFFD), show inhibition/degradation effects on amyloid beta fibrils. Herein, a mathematical model has been proposed. The model simulates Aβ aggregation and inhibitory/degradative action of peptide inhibitors on Aβ fibrillation. Model parameters are tuned by curve fitting the experimental data. The tuned model is used to predict experimental data at different initial dose/fibril concentrations. Model predicted results are observed to be in good agreement with the reported experimental data, demonstrating model's applicability at the molecular level. Sensitivity analyses of the model parameters on the fibril concentration further establish the robustness of the proposed model.

Sufentanil enhances the cortical neurogenesis of rats with traumatic brain injury via PI3K/AKT signal pathway.

This study aimed to explore the effects of Sufentanil on the cortical neurogenesis of rats with traumatic brain injury (TBI) and investigate the potential mechanisms. Rats with TBI model were prepared and divided into sham + vehicle, TBI + vehicle, TBI + Sufentanil and TBI + Sufentanil + LY294002 (PI3K/AKT signal pathway inhibitor) four groups. The oxidative stress, inflammation, nerve cell damage, melatonin, brain-derived neurotrophic factor (BDNF), neuron regeneration and p-AKT protein level in the cortex were detected with ELISA, TUNEL, qRT-PCR, immunofluorescence and Western blot. Pain behavioral test was assessed with mechanical withdrawal threshold (MWT). The results showed Sufentanil significantly decreased the oxidative stress and inflammation levels, increased melatonin and BDNF levels, protected the nerve cells from damage, enhanced the regeneration of immature or mature neurons and the p-AKT protein expression in the cortex, and boosted MWT in TBI rats. While the rats with TBI were treated with LY294002 and Sufentanil together, the abovementioned effects of Sufentanil on the TBI rats were partially reversed. Our results indicate Sufentanil enhances the cortical neurogenesis and inhibits mechanical allodynia of rats with TBI through suppressing the oxidative stress, inflammation response and increasing the melatonin and BDNF levels partly via PI3K/AKT signal pathway.

Extracellular baskets in inner hair cells and perineuronal nets in auditory nerves: Changes in noise-induced hearing loss rats.

The extracellular baskets of cochlear inner hair cell (IhC) ribbon synapses have been suggested to regulate synaptic coupling. This study aimed to investigate the expression of components of the extracellular baskets of the IhCs, chondroitin sulfate proteoglycans (CSPGs) and a hyaluronan and proteoglycan link protein 1 (HAPLN1) in the cochlea and auditory nerve. In addition, changes in CSPGs and HAPLN1 in noise-injured cochleae were examined. The expression of CSPGs, including aggrecan (ACAN), brevican (BCAN), neurocan (NCAN), and HAPLN1, was evaluated in the cochleae of 2-month-old Sprague-Dawley (SD) rats. The expression of CSPGs and HAPLN1 in cochleae and auditory nerves was compared to that in 3-month-old noise-exposed SD rats during the developmental period. The cochlear immunohistochemistry (IHC) and cochlear whole mount immunofluorescence studies were conducted for ACAN, BCAN, NCAN, and HAPLN1. To examine the large ganglial cells in auditory nerves, IHC was conducted for parvalbumin (PV), glutamate decarboxylase 67 (GAD67), postsynaptic density protein 95 (PSD95), and glial fibrillary acidic protein (GFAP). In situ hybridization was performed for BCAN. ACAN, BCAN, and HAPLN1 expression was detected in the IhCs and was decreased tendency in noise-injured cochleae. In the spiral ganglial cell (SGC) region, ACAN and NCAN were expressed without the expression of BCAN. In auditory nerves, large ganglionic cells (LGCs) are encased with perineuronal nets (PNNs), which express PV, GAD67, and PSD95. The mRNA expression of BCAN was noted in SGCs and glial cells of auditory nerves. The extracellular baskets of IhCs revealed the expression of CSPGs and HAPLN1, which was attenuated in noise-exposed cochleae. In auditory nerves, PV-positive LGCs with inhibitory synapses presented PNNs. The protein expression of BCAN was restricted to the extracellular baskets of IhC but not to the SGC region. However, the mRNA expression of BCAN in SGCs was not affected.

Research on the protective effect of Rhizoma of Anemarrhena asphodeloides on TMT induced AD mice model based on network pharmacology combined with in vitro and in vivo experimental validation.

Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of Anemarrhena asphodeloides (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration. To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice. The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by l-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22cells were detected with the 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation. RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. In vivo, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. In vitro, RAA-S reduced HT22cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22cells. RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.

Brain-targeted M2 macrophage membrane-hybrid biomimetic liposomes for treatment of traumatic brain injury.

Traumatic brain injury (TBI) is highly incidental but effective solutions are absent. Moreover, the secondary injury following TBI is arising due to the Ca2+ influx of injured neural cells. Here, a Ca2+ influx inhibitor, nimodipine, was loaded in M2 macrophage membrane-hybrid biomimetic liposomes (NM2Ls). NM2Ls significantly inhibited the influx of Ca2+ into inflammatory neural cells and reduced the expression of inflammatory factors. More importantly, intravenously injected NM2Ls avoided the clearance of the immune system and targeted the brain via CCR2 following TBI; the inflammation in the brain was greatly alleviated in the TBI mouse model. NM2Ls improved the long-term learning and memory abilities as well as the motor abilities of TBI mice. Oxidative stress indicators were reduced and the repair of nerve cells was improved. NM2Ls is a promising brain-targeted medicine by the biomembrane biomimetic strategy.

Multiple Structural States in an Intrinsically Disordered Protein, SNAP-25, Using Circular Dichroism.

SNAP-25, together with other SNARE proteins, drives fusion of synaptic vesicles with the nerve cell membrane leading to neurotransmitter release. It is unique in contributing two α-helices to the four-helix bundle known as the SNARE complex. Complex formation drives fusion as these proteins transform from a disordered-to-ordered (coiled-coil) state. SNAP-25 has two isoforms, -25A and -25B, but little is known of any structural differences, nor are there extensive reports of the structures of its two helical domains, SN1 and SN2. Thus, the benefit of having two distinct isoforms of SNAP-25, each with two distinct domains, is unknown. Here, we use Circular Dichroism (CD) Spectroscopy and Mass Spectrometry (MS) to further characterize the secondary structure of SNAP-25A, SNAP-25B, SN1, SN2, and a cysteine-free version of SNAP-25A. We demonstrate that these proteins undergo structural transitions, with changing fractions of α-helix, β-sheet, and random-coil. These different structures can be induced by varying the environmental conditions of ionic strength, pH, temperature, or redox state. We use triangle plots to directly display the change in ternary composition following changes in these four parameters. We report that SNAP-25A and SNAP-25B make distinctly different structural changes. We show that the secondary structure of SN1 is more variable than SN2. These data add to the ongoing literature characterizing SNAP-25 as an intrinsically disordered protein that is sensitive to environmental conditions in neuronal cells and may function as a redox sensor to modulate neurotransmitter release.

The transformative impact of the mediterranean diet and physical activity on Alzheimer’s disease

Alzheimer's Disease (AD) is a neurodegenerative condition that affects millions of people worldwide, being responsible for most cases of dementia. This disease, characterized by progressive cognitive decline, significantly impacts the quality of life of patients and their families. Amid the search for effective treatments, non-pharmacological interventions, such as the Mediterranean diet and physical activity, emerge as promising approaches for the prevention and management of Alzheimer's. Mediterranean Diet: Nutrition for Brain Health: The Mediterranean diet, which originates from countries such as Greece, Italy, and Spain, is recognized for its balanced dietary pattern, consisting of foods rich in neuroprotective nutrients. Among its main components are fruits, vegetables, whole grains, olive oil, fish, nuts, and red wine in moderation. These foods provide antioxidants, omega-3 fatty acids, vitamins, and polyphenols, which are essential for fighting oxidative stress and inflammation in the brain. Scientific research shows that adherence to the Mediterranean diet is associated with a lower risk of developing Alzheimer's and other neurodegenerative diseases. individuals who strictly follow this dietary pattern are 40% less likely to develop dementia compared to those who consume Western diets, rich in saturated fats and refined sugars The antioxidant role of the diet is critical for brain health, as it reduces damage caused by free radicals. Omega-3 fatty acids, present in fatty fish such as salmon and tuna, are known to promote synaptic plasticity and communication between neurons. In addition, olive oil, rich in anti-inflammatory compounds, helps protect nerve cells against inflammatory processes that contribute to the progression of AD. Physical Activity: Movement and Neuroprotection: Regular physical exercise is an equally effective intervention in combating brain degeneration. Exercise, especially aerobics, promotes neurogenesis in the hippocampus, a region responsible for memory and learning, showed that regular exercise increases hippocampal volume in older adults, slowing cognitive decline. Longitudinal studies, such as the one indicate that physical activity improves executive functions, memory, and attention in older adults with mild cognitive impairment. In addition, exercise reduces metabolic risk factors, such as obesity, hypertension, and diabetes, which are directly associated with the progression of AD. Point out that up to a third of Alzheimer's cases could be avoided through interventions aimed at reducing these factors.

Lipid Biochemistry and its Role in Human Diseases.

Lipids play a variety of roles in living systems. They are a source of extremely high energy and a part of almost all signaling and biological processes. Despite the liver being the hub of lipid metabolism, lipid metabolism occurs across the human body. Any perturbation in the lipid metabolism or lipid storage systems can lead to diseases or disorders that can hamper the normal functioning of the human body. Lipids have been explored for their role in cancers. The intake of saturated fatty acids has been found to increase the metastasis and growth of cancerous cells. The role of lipids has also been studied in brain diseases. In Tay-Sachs disease, the inability to metabolize GM2 ganglioside alters normal nerve cell functioning. Similarly, lipids also play critical roles in Parkinson's and Alzheimer's disease. Moreover, atherosclerosis is a leading cause of cardiovascular diseases and brain stroke. Dyslipidemia or excess fatty acids is a leading cause of non-alcoholic fatty liver disease, insulin resistance, and diabetes mellitus. Dyslipidemia also leads to jaundice, which, in turn, can seriously damage the kidneys. This review focuses on the various human diseases occurring because of lipid metabolism.

Tinosinenside A inhibits neuroinflammation and protects HT22 cells by suppressing the TLR4/NF-κB/NLRP3 signaling pathway in BV2 cells.

Microglia-mediated neuroinflammation plays a crucial role in Alzheimer's disease (AD). Tinosinenside A (Tis A) is a novel sesquiterpene glycoside isolated from the dried rattan stem of Tinospora sinensis (Lour.) Merr. Tis A exhibited anti-inflammatory and neuroprotective activities in vitro. However, the mechanism underlying the inhibition of neuroinflammation and protection of nerve cells remains obscure. This study used lipopolysaccharide (LPS)-induced inflammatory response in BV2 cells to simulate a neuroinflammatory model and used Aβ1-42-induced HT22 cells to establish an AD cell model, aiming to investigate the efficacy and mechanism of Tis A through anti-neuroinflammation to protect nerve cells. Tis A had no effect on the proliferation of BV2 and HT22 cells at the tested concentrations. The time- and dose-dependent effects of Tis A on the LPS-induced inflammatory response of BV2 cells demonstrated that the best anti-inflammatory efficacy appeared after 12h of pretreatment. Tis A inhibited the gene levels of TNF-α, IL-6, IL-1β, iNOS, and IL-10 while enhancing the gene levels of IL-4 and TGF-β. Additionally, Tis A reduced the gene expression levels of CD16 and CD32 and increased the CD36 and CD206 gene expression levels. It also downregulated the protein expression of Iba-1 and iNOS while upregulating CD206. Tis A obviously inhibited NLRP3 gene and protein expression in LPS-stimulated BV2 cells. The inhibitory effect of Tis A on NLRP3 was counteracted by the NLRP3 activator nigericin and overexpression plasmid GV358. Tis A inhibits NLRP3 protein expression to reduce the assembly of NLRP3/ASC/Caspase-1 inflammasome, then regulates the TLR4/NF-κB/NLRP3 signaling pathway. It regulates microglia activation and M1/M2 phenotypic polarization, then inhibits the production of inflammatory factors, and reduces the apoptosis rate of HT22 cells under inflammatory conditions, improving the survival rate of nerve cells to protect neurons.

Polyphenylalanine-Baicalein Nanomicelles Reduce Nerve Cell Apoptosis and Inflammation to Enhance Neuroprotection and Poststroke Rehabilitation.

Cerebral ischemic stroke, neuronal death, and inflammation bring difficulties in neuroprotection and rehabilitation. In this study, we developed and designed the ability of natural lactoferrin-polyethylene glycol-polyphenylalanine-baicalein nanomicelles (LF-PEG-PPhe-Bai) to target and reduce these pathological processes, such as neurological damage and cognitive impairment in the stages of poststroke. Nanomicelles made from biocompatible materials have improved bioavailability and targeted distribution to afflicted brain areas. The results showed that LF-PEG-PPhe-Bai greatly improved the antioxidation, antiapoptosis, and anti-inflammation activity in vitro. Meanwhile, LF-PEG-PPhe-Bai improved the behavioral and cognitive impairment of 2-VO model mice, protected nerve cells in the hippocampus, and reduced inflammation at the brain injury site in vivo. In conclusion, LF-PEG-PPhe-Bai nanomicelles are employed for enhancing neuroprotection and poststroke rehabilitation. The development of this technology might provide a new technique for neural repair after ischemia in the future.

Halting Pancreatic Ductal Adenocarcinoma Progression and Metastasis by Neuron-Inhibitory Liposomes.

Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive malignancy. The occurrence of perineural invasion is associated with neuropathic pain and poor prognosis of PDAC, underscoring the active participation of nerves and their potential as therapeutic targets. Lidocaine is a local anesthetic with antitumor properties in some tumors in the clinic. Nevertheless, its clinical application in PDAC is constrained by the insufficient tumor accumulation and potential neurovirulence associated with a high-dose regimen. Here, a tumor microenvironment-targeted and -responsive liposome was constructed to deliver lidocaine for restraining PDAC growth through single nerve regulation. By conjugation of a collagen binding peptide, the pH-responsive liposomes accumulate in the extracellular matrix. The released lidocaine selectively reduces neurite length and density, thereby indirectly halting the progression and metastasis of PDAC in an orthotopic mouse model without noticeable adverse effects. This study highlights the potential of anesthetic-based nanomodulation of crosstalk between nerve and tumor cells for PDAC treatment.

Transforming tomatoes into GABA-rich functional foods through genome editing: A modern biotechnological approach.

Gamma-aminobutyric acid (GABA) functions as an inhibitory neurotransmitter which blocks the impulses between nerve cells in the brain. Due to the increasing awareness about the health promoting benefits associated with GABA, it is also artificially synthesized and consumed as a nutritional supplement by people in some regions of the world. Though among the fresh vegetables, tomato fruits do contain a comparatively higher amount of GABA (0.07 to 2.01mgg-1 FW), it needs to be further enhanced to fully impart its potential health benefits. Achieving this feat through classical breeding approaches is time and resource consuming, and is also associated with linkage drag. On the other hand, precise targeting of specific sites in the genome with less off- target effects is mediated by CRISPR/Cas9 genome editing tool and is widely used to overcome the barriers associated with traditional breeding approaches. Combining genome editing with speed breeding techniques can enable the rapid development of GABA-rich tomato cultivars, paving a way to unlock a new era of functional foods, where every bite contributes to cognitive well-being and holistic health. This review highlights the significance of GABA boosted functional foods and explores the potential of CRISPR/Cas9 technology for developing GABA enriched tomatoes.

Ligustrazine hydrochloride Prevents Ferroptosis by Activating the NRF2 Signaling Pathway in a High-Altitude Cerebral Edema Rat Model

High-altitude cerebral edema (HACE) is a disorder caused by low pressure and hypoxia at high altitudes. Nevertheless, as of now, there is still a scarcity of safe and effective prevention and treatment methods. The active component of Ligusticum Chuanxiong, namely Ligustrazine hydrochloride (LH), has shown potential in the prevention and treatment of HACE due to its anti-inflammatory, antioxidant, and neuroprotective effects in nervous system disorders. Consequently, the potential protective effect of LH on HACE and its mechanism still need to be further explored. Prior to modeling, 90 male Sprague-Dawley rats were pretreated with different doses of drugs, including LH (100 mg/kg and 50 mg/kg), dexamethasone (4 mg/kg), and ML385 (30 mg/kg). Subsequently, the pretreated rats were placed in a low-pressure anoxic chamber simulating a plateau environment to establish the rat HACE model. The effects and mechanisms of LH on HACE rats were further elucidated through determination of brain water content, HE staining, ELISA, immunofluorescence, molecular docking, molecular dynamics simulation, western blot, and other techniques. The results showed, first of all, that LH pretreatment can effectively reduce brain water content; down-regulate the expression of AQP4, HIF-1α, and VEGF proteins; and alleviate damage to brain tissue and nerve cells. Secondly, compared with the HACE group, LH pretreatment can significantly reduce MDA levels and increase GSH and SOD levels. Additionally, LH decreased the levels of inflammatory factors IL-1β, IL-6, and TNF-α; reduced total iron content in brain tissue; increased the expression of ferroptosis-related proteins such as SLC7A11, GPX4, and FTH1; and alleviated ferroptosis occurrence. Molecular docking and molecular dynamics simulations show that LH has a strong binding affinity for NRF2 signaling. Western blot analysis further confirmed that LH promotes the translocation of NRF2 from the cytoplasm to the nucleus and activates the NRF2 signaling pathway to exert an antioxidant effect. The NRF2 inhibitor ML385 can reverse the anti-oxidative stress effect of LH and its protective effect on HACE rat brain tissue. In summary, LH may have a protective effect on HACE rats by activating the NRF2 signaling pathway, inhibiting ferroptosis, and resisting oxidative stress.

Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair

Plp1-lineage Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the transition process initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven Shh enhancers. Collectively, these findings depict an injury-specific niche signal-mediated Plp1-lineage cells transition towards Gli1+ MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.

The Cell States of Sea Urchin During Metamorphosis Revealed by Single-Cell RNA Sequencing

Metamorphosis is a key process in the life history of sea urchin Heliocidaris crassispina. However, the understanding of its molecular mechanisms is still lacking, especially the basic cell biology pre-metamorphosis and post-metamorphosis. Therefore, we employed single-cell RNA sequencing to delineate the cellular states of larvae and juveniles of H. crassispina. Our investigation revealed that the cell composition in sea urchins comprises six primary populations, encompassing nerve cells, skeletogenic cells, immune cells, digestive cells, germ cells, and muscle cells. Subsequently, we identified subpopulations within these cells. Our findings indicated that the larval peripheral nerves were discarded during metamorphosis. A decrease in the number of spicules was observed during this process. Additionally, we examined the differences between larval and adult pigment cells. Meanwhile, cellulase is highlighted as an essential factor for the development of competent juveniles. In summary, this study not only serves as a valuable resource for future research on sea urchins but also deepens our understanding of the intricate metamorphosis process.