Discovery of 7-alkoxybenzofurans as PDE4 inhibitors with hepatoprotective activity in D-GalN/LPS-induced hepatic sepsis.

Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.

Phelligridimer A enhances the expression of mitofusin 2 and protects against cerebral ischemia/reperfusion injury.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play pivotal roles in the pathology of cerebral ischemia. In this study, we investigated whether phelligridimer A (PA), an active compound isolated from the medicinal and edible fungus Phellinus igniarius, ameliorates ischemic cerebral injury by restoring mitochondrial function and restricting ER stress. An in vitro cellular model of ischemic stroke-induced neuronal damage was established by exposing HT-22 neuronal cells to oxygen-glucose deprivation/reoxygenation (OGD/R). An in vivo animal model was established in rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). The results showed that PA (1-10 µM) dose-dependently increased HT-22 cell viability, reduced OGD/R-induced lactate dehydrogenase release, and reversed OGD/R-induced apoptosis. PA reduced OGD/R-induced accumulation of reactive oxygen species, restored mitochondrial membrane potential, and increased ATP levels. Additionally, PA reduced the expression of the 78-kDa glucose-regulated protein (GRP78) and the phosphorylation of inositol-requiring enzyme-1α (p-IRE1α) and eukaryotic translation-initiation factor 2α (p-eIF2α). PA also inhibited the activation of the mitogen-activated protein kinase (MAPK) pathway in the OGD/R model. Moreover, treatment with PA restored the expression of mitofusin 2 (Mfn-2), a protein linking mitochondria and ER. The silencing of Mfn-2 abolished the protective effects of PA. The results from the animal study showed that PA (3-10 mg/kg) significantly reduced the volume of cerebral infarction and neurological deficits, which were accompanied by an increased level of Mfn-2, and decreased activation of the ER stress in the penumbra of the ipsilateral side after MCAO/R in rats. Taken together, these results indicate that PA counteracts cerebral ischemia-induced injury by restoring mitochondrial function and reducing ER stress. Therefore, PA might be a novel protective agent to prevent ischemia stroke-induced neuronal injury.

Inhibition of phosphodiesterase 4 attenuates aquaporin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury.

We have previously shown that phosphodiesterase 4 (PDE4) inhibition protects against neuronal injury in rats following middle cerebral artery occlusion/reperfusion (MCAO/R). However, the effects of PDE4 on brain edema and astrocyte swelling are unknown. In this study, we showed that inhibition of PDE4 by Roflumilast (Roflu) reduced brain edema and brain water content in rats subjected to MCAO/R. Roflu decreased the expression of aquaporin 4 (AQP4), while the levels of phosphorylated protein kinase B (Akt) and forkhead box O3a (FoxO3a) were increased. In addition, Roflu reduced cell volume and the expression of AQP4 in primary astrocytes undergoing oxygen and glucose deprivation/reoxygenation (OGD/R). Consistently, PDE4B knockdown showed similar effects as PDE4 inhibition; and PDE4B overexpression rescued the inhibitory role of PDE4B knockdown on AQP4 expression. We then found that the effects of Roflu on the expression of AQP4 and cell volume were blocked by the Akt inhibitor MK2206. Since neuroinflammation and astrocyte activation are the common events that are observed in stroke, we treated primary astrocytes with interleukin-1ß (IL-1ß). Astrocytes treated with IL-1ß showed decreased AQP4 and phosphorylated Akt and FoxO3a. Roflu significantly reduced AQP4 expression, which was accompanied by increased phosphorylation of Akt and FoxO3a. Furthermore, overexpression of FoxO3a partly reversed the effect of Roflu on AQP4 expression. Our findings suggest that PDE4 inhibition limits ischemia-induced brain edema and astrocyte swelling via the Akt/FoxO3a/AQP4 pathway. PDE4 is a promising target for the intervention of brain edema after cerebral ischemia.

Dynamic Electrostatic Interfacial Engineering for Block Copolymer Microparticles with Reversible Structures.

Responsive nanoparticle surfactants (NPSs) can dynamically and reversibly modulate the interfacial interactions between incompatible components, which are essential in the interfacial catalysis, corrosion, and self-assembly of block copolymers (BCPs). However, NPSs with stimuli-responsive behavior often involve tedious chemical synthesis and surface modifications. Herein, we propose a strategy to in situ construct a kind of dynamic and reversible NPSs by the interfacial electrostatic interaction between the negatively charged nanoparticles (NPs) and the positively charged homopolymers. The NPSs assembled at the oil/water interface reduce the interfacial tension and direct the confined assembly of BCP. Meanwhile, the dynamic NPSs can be disassembled by increasing the pH value or introducing competitive electrostatic attractions, which can dynamically and reversibly change the interfacial properties as well as the alignment of polymer chains, enabling BCP microparticles with reversibly switchable lamellar and cylindrical structures. Furthermore, by the introduction of aggregation-induced emission luminogens as tails to the NPSs, the reversible transformation of BCP microparticles can be visualized by fluorescence emission, which is dependent on the nanostructures of microparticles. This work establishes a concept for dynamically manipulating interfacial interactions and reversibly switching BCP microparticles without time-consuming NPS synthesis, showing promising applications in the fabrication of smart materials with switchable structures and properties.

Microglia nuclear receptor corepressor 1 deficiency alleviates neuroinflammation in mice.

Given the established role of nuclear receptor corepressor 1 (NCoR1) in sensing environmental cues and the importance of inflammation in neurodegenerative diseases, elucidation of NCoR1 involvement in neuroinflammation has notable implications. Yet, its regulatory mechanism remains largely unclear. Under in vitro conditions, NCoR1 expression peaked and then decreased at 12 h after lipopolysaccharides (LPS) stimulation in BV2 cells, However, NCoR1 knockdown using si-RNA attenuated microglial inflammation, evident by reduced the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), phosphorylated-JNK and high mobility group box-1 (HMGB1). Furthermore, NCoR1 suppression could counteract the decline in mitochondrial membrane potential while simultaneously enhancing the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Under in vivo conditions, microglia-specific NCoR1 knockout (MNKO) mice after LPS injections alleviated the symptoms of anhedonia, diminished autonomic activity and cognitive impairment. Additionally, MNKO mice showed attenuation of microglial activation, downregulated HMGB1 and COX2, and upregulated PGC-1α expression in the cortex. In conclusion, these findings suggest that NCoR1 deficiency leads to a modest reduction in neuroinflammation, possibly attributed to the increased expression of PGC-1α.

Decoding the Pathway-Dependent Self-Assembly of Polymer-Grafted Nanoparticles by Ligand Crystallization.

Functional metamaterials can be constructed by assembling nanoparticles (NPs) into well-ordered structures, which show fascinating properties at different length scales. Using polymer-grafted NPs (PGNPs) as a building block, flexible composite metamaterials can be obtained, of which the structure is significantly affected by the property of polymer ligands. Here, it is demonstrated that the crystallization of polymer ligands determines the assembly behavior of NPs and reveal a pathway-dependent self-assembly of PGNPs into different metastructures in solution. By changing the crystallization degree of polymer ligands, the arrangement structure of NPs can be tailored. When the polymer ligands highly crystallize, the PGNPs assemble into diamond-shaped platelets, in which the NPs arrange disorderedly. When the polymer ligands lowly crystallize, the PGNPs assemble into highly ordered 3D superlattices, in which the NPs pack into a body-centered-cubic structure. The structure transformation of PGNP assemblies can be achieved by thermal annealing to regulate the crystallization of polymer ligands. Interestingly, the diamond-shaped platelets remain "living" for seeded epitaxial growth of newly added crystalline species. This work demonstrates the effects of ligand crystallization on the crystallization of NP, providing new insights into the structure regulation of metamaterials.

TMT-based quantitative proteomics analysis of neuroprotective effects of Forsythoside A on the MPTP-induced Parkinson's disease mouse model.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characteristized by the presence of dyskinesia and the progressive loss of dopaminergic neurons. Although certain drugs can mitigate the symptoms of PD, they are unable to delay the disease progression, and their prolonged use may result in complications. Therefore, there exists an urgent necessity to identify potential agents that can effectively delay PD progression with fewer side effects. Recent research has unveiled that several traditional Chinese medicines (TCM) exhibit neuroprotective properties in various models pertinent to PD. Forsythoside A (FSA), the primary bioactive compound derived from TCM Lianqiao, has undergone extensive research in animal models of Alzheimer's disease and cerebral ischemia. However, the investigation into the impact of FSA on PD is limited in existing research. In this study, we aimed to evaluate the neuroprotective effects of FSA on MPTP-induced PD mouse model. FSA demonstrated significant improvements in the behavioral and neuropathological changes triggered by MPTP in mice. Furthermore, it exerted a suppressive effect on the activations of astrocyte and microglia. Meanwhile, Tandem mass tag (TMT)-based quantitative proteomics of striatal tissue and bioinformatics analysis were performed to elucidate the underlying mechanisms of FSA on PD mouse model. Proteomics demonstrated a total of 68 differentially expressed proteins (DEPs) were identified between HFSA and MPTP groups including 26 upregulated and 42 downregulated. Systematic bioinformatics analysis of the 68 DEPs illustrated that they were predominantly related to estrogen signaling pathway and calcium signaling pathway. The related DEPs (PLCß4, Grm2, HPAC and Cox4i1) expression levels were verified by Western blot. FSA effectively restored the altered expression of the four DEPs induced by MPTP. Summarily, FSA exerted remarkable neuroprotective effects in MPTP-induced mice. Further, our research may provide proteomics insights that contribute to the further exploration of FSA as a potential treatment for PD.

Involvement of CKS1B in the anti-inflammatory effects of cannabidiol in experimental stroke models.

We have previously demonstrated that treatment with cannabidiol (CBD) ameliorates mitochondrial dysfunction and attenuates neuronal injury in rats following cerebral ischemia. However, the role of CBD in the progression of ischemic stroke-induced inflammation and the molecules involved remain unclear. Here, we found that CBD suppressed the production of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), reduced the activation of microglia, ameliorated mitochondrial deficits, and decreased the phosphorylation of nuclear factor κ-B (NF-κB) in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cyclin-dependent kinase regulatory subunit 1B (CKS1B) expression was decreased in BV-2 cells following OGD/R and this reduction was blocked by treatment with CBD. Knockdown of CKS1B increased the activation of microglia and enhanced the production of IL-1ß and TNF-α in BV-2 cells treated with CBD. Moreover, CKS1B knockdown exacerbated mitochondrial deficits and increased NF-κB phosphorylation. CBD treatment also ameliorated brain injury, reduced neuroinflammation, and enhanced the protein levels of mitochondrial transcription factor A and CKS1B in rats following middle cerebral artery occlusion/reperfusion. These data identify CKS1B as a novel regulator of neuroinflammation; and reveals its involvement in the anti-inflammatory effects of CBD. Interventions targeting CKS1B expression are potentially promising for treating in ischemic stroke.

Clinic choice of long or short segment pedicle screw-rod fixation in the treatment of thoracolumbar burst fracture: From scan data to numerical study.

Based on computerized tomography scanning images of human lumbar vertebrae, finite element (FE) analysis is performed to predict the stress of pedicle screws, rods, and fractured vertebra as well as the displacement of fractured vertebra after internal fixation treatment of thoracolumbar burst fracture. A three-dimensional FE model of L1-L5 lumbar vertebrae with L3 burst fracture has been established and four fixation methods, namely, short segment cross- and trans-injured vertebrae, long segment cross- and trans-injured vertebrae fixations, have been adopted to perform posterior pedicle fixation. The stress distributions of the screws, rods, and fractured vertebra and the total deformation of the fractured vertebra are investigated under six different physiological motions. From the view of the stress on the screw-rod system and the deformation of the fractured vertebral body, the long segment cross-injured vertebra fixation has the best mechanical performance, followed by the long segment trans-injured vertebra fixation, and then the short segment fixation trans-injured vertebra. The short segment fixation cross-injured vertebra performs the worst. Among the six motions, the forward flexion movement has the greatest impact on the screw-rod system and the fractured vertebra. However, the rotation motion greatly affects the stress of the screw in the long segment fixation. This indicates that the longer the fixed segment is, the more susceptible it is to human rotation. Thus, for patients with severe fracture, the long segment cross-injured vertebra is preferred. On the contrary, the short segment trans-injured vertebra fixation is optimal.

Large-Area Arrays of Polymer-Tethered Gold Nanorods with Controllable Orientation and Their Application in Nano-Floating-Gate Memory Devices.

In this work, it is reported that large-area (centimeter-scale) arrays of non-close-packed polystyrene-tethered gold nanorod (AuNR@PS) can be prepared through a liquid-liquid interfacial assembly method. Most importantly, the orientation of AuNRs in the arrays can be controlled by changing the intensity and direction of electric field applied in the solvent annealing process. The interparticle distance of AuNR can be tuned by varying the length of polymer ligands. Moreover, the AuNR@PS with short PS ligand are favorited to form orientated arrays with the assistance of electric field, while long PS ligands make the orientation of AuNRs difficult. The orientated AuNR@PS arrays are employed as the nano-floating gate of field-effect transistor memory device. Tunable charge trapping and retention characteristics in the device can be realized by electrical pulse with visible light illumination. The memory device with orientated AuNR@PS array required less illumination time (1 s) at the same onset voltage in programming operation, compared to the control device with disordered AuNR@PS array (illumination time: 3 s). Moreover, the orientated AuNR@PS array-based memory device can maintain the stored data for more than 9000 s, and exhibits stable endurance characteristic without significant degradation in 50 programming/reading/erasing/reading cycles.

Numerical simulation and experimental validation of thrombolytic therapy for patients with venous isomer and normal venous valves.

Thrombus is an extremely dangerous factor in the human body that can block the blood vessel. Once thrombosis happens in venous of lower limbs, local blood flow is impeded. This leads to venous thromboembolism (VTE) and even pulmonary embolism. In recent years, venous thromboembolism has frequently occurred in a variety of people, and there is no effective treatment for patients with different venous structures. For the patients with venous isomer with single valve structure, we establish a coupled computational model to simulate the process of thrombolysis with multi-dose treatment schemes by considering the blood as non-Newtonian fluid. Then, the corresponding in vitro experimental platform is built to verify the performance of the developed mathematical model. At last, the effects of different fluid models, valve structures and drug doses on thrombolysis are comprehensively studied through numerical and experimental observations. Comparing with the experimental results, the relative error of blood boosting index (BBI) obtained from non-Newtonian fluid model is 11% smaller than Newtonian fluid. In addition, the BBI from venous isomer is 1300% times stronger than patient with normal venous valve while the valve displacement is 500% times smaller. As consequence, low eddy current and strong molecular diffusion near the thrombus in case of isomer promote thrombolysis rate up to 18%. Furthermore, the 80 µM dosage of thrombolytic drugs gets the maximum thrombus dissolution rate 18% while the scheme of 50 µM doses obtains a thrombolysis rate of 14% in case of venous isomer. Under the two administration schemes for isomer patients, the rates from experiments are around 19.1% and 14.9%, respectively. It suggests that the proposed computational model and the designed experiment platform can potentially help different patients with venous thromboembolism to carry out clinical medication prediction.

Polymeric Memristor Based Artificial Synapses with Ultra-Wide Operating Temperature.

Neuromorphic electronics, being inspired by how the brain works, hold great promise to the successful implementation of smart artificial systems. Among several neuromorphic hardware issues, a robust device functionality under extreme temperature is of particular importance for practical applications. Given that the organic memristors for artificial synapse applications are demonstrated under room temperature, achieving a robust device performance at extremely low or high temperature is still utterly challenging. In this work, the temperature issue is addressed by tuning the functionality of the solution-based organic polymeric memristor. The optimized memristor demonstrates a reliable performance under both the cryogenic and high-temperature environments. The unencapsulated organic polymeric memristor shows a robust memristive response under test temperature ranging from 77 to 573 K. Utilizing X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectrometry (ToF-SIMS) depth profiling, the device working mechanism is unveiled by comparing the compositional profiles of the fresh and written organic polymeric memristors. A reversible ion migration induced by an applied voltage contributes to the characteristic switching behavior of the memristor. Herein, both the robust memristive response achieved at extreme temperatures and the verified device working mechanism will remarkably accelerate the development of memristors in neuromorphic systems.

Nanostructure-free crescent-shaped microparticles as full-color reflective pigments.

Structural colors provide a promising visualization with high color saturation, iridescent characteristics, and fade resistance. However, pragmatic uses are frequently impeded by complex manufacturing processes for sophisticated nanostructures. Here, we report a facile emulsion-templating strategy to produce crescent-shaped microparticles as structural color pigments. The micro-crescents exhibit brilliant colors under directional light originating from total internal reflections and optical interferences in the absence of periodic nanostructures while being transparent under ambient light. The colors are finely tunable by adjusting the size of the micro-crescents, which can be further mixed to enrich the variety. Importantly, the pre-defined convex surface secures high stability of colors and enables structural coloration on target surfaces through direct deposition as inks. We anticipate this class of nanostructure-free structural colorants is pragmatic as invisible inks in particular for anti-counterfeiting patches and color cosmetics with distinctive impressions due to low-cost, scalable manufacturing, unique optical properties, and versatility.

Advances in the development of phosphodiesterase 7 inhibitors.

Phosphodiesterase 7 (PDE7) specifically hydrolyzes cyclic adenosine monophosphate (cAMP), a second messenger that plays essential roles in cell signaling and physiological processes. Many PDE7 inhibitors used to investigate the role of PDE7 have displayed efficacy in the treatment of a wide range of diseases, such as asthma and central nervous system (CNS) disorders. Although PDE7 inhibitors are developed more slowly than PDE4 inhibitors, there is increasing recognition of PDE7 inhibitors as potential therapeutics for no nausea and vomiting secondary. Herein, we summarized the advances in PDE7 inhibitors over the past decade, focusing on their crystal structures, key pharmacophores, subfamily selectivity, and therapeutic potential. Hopefully, this summary will lead to a better understanding of PDE7 inhibitors and provide strategies for developing novel therapies targeting PDE7.

Electric, magnetic, and shear field-directed assembly of inorganic nanoparticles.

Ordered assemblies of inorganic nanoparticles (NPs) have shown tremendous potential for wide applications due to their unique collective properties, which differ from those of individual NPs. Various assembly methods, such as external field-directed assembly, interfacial assembly, template assembly, biomolecular recognition-mediated assembly, confined assembly, and others, have been employed to generate ordered inorganic NP assemblies with hierarchical structures. Among them, the external field-directed assembly method is particularly fascinating, as it can remotely assemble NPs into well-ordered superstructures. Moreover, external fields (e.g., electric, magnetic, and shear fields) can introduce a local and/or global field intensity gradient, resulting in an additional force on NPs to drive their rotation and/or translation. Therefore, the external field-directed assembly of NPs becomes a robust method to fabricate well-defined functional materials with the desired optical, electronic, and magnetic properties, which have various applications in catalysis, sensing, disease diagnosis, energy conversion/storage, photonics, nano-floating-gate memory, and others. In this review, the effects of an electric field, magnetic field, and shear field on the organization of inorganic NPs are highlighted. The methods for controlling the well-ordered organization of inorganic NPs at different scales and their advantages are reviewed. Finally, future challenges and perspectives in this field are discussed.

MicroRNA-124-3p alleviates cerebral ischaemia-induced neuroaxonal damage by enhancing Nrep expression.

OBJECTIVE: Ischaemic stroke has a high death rate and frequently results in long-term and severe brain damage in survivors. miRNA-124-3p (miR-124-3p) treatment has been suggested to reduce ischaemia and play a vital function in avoiding neuron death. An investigation of the role of miR-124-3p, in the ischaemia damage repair or protection in the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reperfusion (OGD/R) model, was the purpose of this research. METHODS: The expression of miRNA and mRNA in the MCAO model was predicted using bioinformatics analysis. The OGD/R neuronal model was developed. We examined the influence of a number of compounds on the OGD/R model in vitro using gain- and loss-of-function approaches. RESULTS: For starters, miR-124-3p and Nrep level in the MCAO model were found to be lower in the model predicted by bioinformatics than in the sham-operated group. And then in the OGD/R model, miR-124-3p treatment reduced OGD/R neuronal damage, increased neuronal survival, and reduced apoptosis in cell lines. Moreover, we further looked at the impact of miR-124-3p on downstream Rnf38 and Nrep using the OGD/R model. Western blot analysis and dual-luciferase reporter assays indicated that miR-124-3p binds and inhibits Rnf38. Finally, although Nrep expression was reduced in the OGD/R model neuronal model, it was shown that miR-124-3p administration reduced apoptosis and increased neuronal activity, particularly with regard to axon regeneration-related proteins. CONCLUSION: Our studies have shown that miR-124-3p may reduce neuronal injury by preventing Rnf38-mediated effects on the Nrep axis.

Intracellular Activity of Poly (DL-Lactide-co-Glycolide) Nanoparticles Encapsulated with Prothionamide, Pyrazinamide, Levofloxacin, Linezolid, or Ethambutol on Multidrug-Resistant Mycobacterium tuberculosis.

BACKGROUND: Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is a major cause of death amongst tuberculosis patients. Nanomedicine avoids some limitations of conventional drug treatment and increases therapeutic efficacy against bacterial infections. However, the effect of anti-TB drug nanoparticle (NP) compounds in anti-TB regimens against MDR-TB remains unclear. OBJECTIVE: The objective of this article is to prepare levofloxacin, linezolid, ethambutol, prothionamide, and pyrazinamide encapsulated NPs and to evaluate their therapeutic efficacy against MDR-TB in macrophages. METHODS: Drug-loaded PLGA NPs were prepared by the multiple emulsion method. The colocalization, intracellular release, and anti-TB activity of these NPs were investigated on cultured macrophages. The immune phenotype of the macrophages, including their mitochondrial membrane potential, reactive oxygen species (ROS), and nitric oxide (NO) production, was evaluated following treatment with NPs or free drug compounds. RESULTS: All drug-loaded PLGA NPs were spherical in shape, 150 to 210 nm in size, and showed 14.22% to 43.51% encapsulation efficiencies and long-duration release. Drug-loaded PLGA NPs were mainly distributed in the cytoplasm of macrophages, showed high cellular compatibility, and maintained their concentration for at least 13 days. Compared with the free drug compounds, the number of colonies after exposure to PLGA NP compounds was significantly less. The enhanced antibacterial activity of the NP compounds may be due to the enhanced levels of ROS and NO and the increased early apoptosis stress within M. tuberculosis-infected macrophages additionally. CONCLUSION: The application of PLGA NP compounds not only enhances drug efficacy but also induces innate bactericidal events in macrophages, confirming this as a promising approach for MDR-TB therapy.

Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats.

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 µM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD's protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin's binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.

QEEG indices are associated with inflammatory and metabolic risk factors in Parkinson's disease dementia: An observational study.

Background: Quantitative electroencephalography (QEEG) is a reliable and non-invasive diagnostic tool to quantify cortical synaptic injury or loss in the clinical assessment of neurodegenerative diseases, and may be able to differentiate various types of dementia. We investigated if QEEG indices can differentiate Parkinson's Disease (PD) with nondementia (PD-ND) from PD with dementia (PDD), and to determine if QEEG indices correlate with inflammation and lipid metabolism markers in PD. Methods: This clinical study collected data between July 1, 2018 and July 1, 2021 in Zhujiang Hospital of Southern Medical University in China and data was analysed. A total of 125 individuals comprising of 31 PDD, 47 patients with PD-ND and 47 healthy controls were included. We calculated the absolute spectral power (ASP) of frequency bands and the slow-to-fast frequency ratios of specific brain regions. Plasma levels of hypersensitive C-reactive protein (Hs-CRP), superoxide dismutase (SOD), and high-density lipoprotein cholesterol (HDL-C) were measured and correlations with QEEG indices were examined. Findings: A significantly higher ASP of delta frequency especially in the frontal region was observed in patients with PDD compared to PD-ND (P=0.004) and controls (P=0.000). Decreased HDL-C (OR=0.186, P=0.030), and increased Hs-CRP (OR =2.856, P=0.015) were associated with PDD. Frontal-delta ASP was negatively correlated with plasma HDL-C (r=-0.353, P=0.000) and SOD (r=-0.322, P=0.001), and positively correlated with Hs-CRP (r=0.342, P=0.000). Interpretation: We highlight novel correlations between QEEG indices and inflammation and lipid metabolism markers in PD-ND and PDD. QEEG indices, HDL-C and Hs-CRP are potentially useful for the evaluation of PDD. Our current findings suggest that peripheral inflammation might contribute to the pathogenesis of cognitive impairment and EEG slowing in PDD. The mechanism underlying frontal-delta ASP and its correlation with neuro-inflammatory and metabolic markers in PDD should be further investigated. Funding: The National Natural Science Foundation of China (NO: 81873777, 82071414); the Scientific Research Foundation of Guangzhou (NO: 202206010005); the Science and Technology Program of Guangdong of China (NO: 2020A0505100037); the High-level Hospital Construction Research Project of Maoming People's Hospital (NO: xz2020009); the Science and Technology Program of Maoming City (NO: 2021S0026). Dr EK Tan is supported by the National Medical Research Council, Singapore.

Persimmon leaf extract alleviates chronic social defeat stress-induced depressive-like behaviors by preventing dendritic spine loss via inhibition of serotonin reuptake in mice.

BACKGROUND: Fresh or dried Persimmon leaves (Diospyros kaki Thunb.) exhibit preventive effects on cardiovascular and cerebrovascular diseases. However, their antidepressant effects and underlying mechanisms are unclear. Thus, we investigated mechanisms responsible for Persimmon leaf extract (PLE) activity on chronic social defeat stress (CSDS)-induced depressive-like behaviors in mice. METHODS: CSDS was used as a mouse model of depression. We performed the sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) to identify depressive-like behavior. Spine density and dendritic morphology were assessed using Golgi staining. Neurochemicals were quantified by microdialysis, doublecortin by immunofluorescence, and cAMP using an ELISA kit. Finally, the levels of cortical proteins of phosphorylated cAMP-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), postsynaptic density synapsin-1 and protein 95 (PSD95) were quantified by western blot. 16S rRNA gene sequencing was used to detect fecal microbiota. RESULTS: Treatment of CSDS-subjected mice with PLE (30.0-60.0 mg/kg, i.g.) enhanced sucrose preference, decreased immobility times in the TST and FST but did not affect locomotor activity. Furthermore, persistent social defeat stress decreased dendritic spine density and dendritic length in the brain, as well as decreased PSD95 and synapsin-1 expression. PLE, interestingly, inhibited dendritic spine loss and increased synaptic protein levels. PLE also increased brain levels of 5-HT, cAMP, phosphorylated (p)-CREB, BDNF, PSD95, and synapsin-1 in mice subjected to CSDS. Furthermore, PLE increased their doublecortin-positive cell count in the hippocampal dentate gyrus. CSDS mice represented a distinct fecal microbiota cluster which differed compared with normal C57BL/6J mice, and the phenotype was rescued by PLE. CONCLUSIONS: PLE alleviated CSDS-induced depressive behaviors and spinal damage by suppressing serotonin reuptake and activating the cAMP/CREB/BDNF signaling pathway. Simultaneously, PLE influenced the composition of the fecal microbiota in CSDS-subjected mice.