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Hyperinflammation is related to the development of COVID-19. Resveratrol is considered an anti-inflammatory and antiviral agent. Herein, we used a network pharmacological approach and bioinformatic gene analysis to explore the pharmacological mechanism of Resveratrol in COVID-19 therapy. Potential targets of Resveratrol were obtained from public databases. SARS-CoV-2 differentially expressed genes (DEGs) were screened out via bioinformatic analysis Gene Expression Omnibus (GEO) datasets GSE147507, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; then, protein-protein interaction network was constructed. The common targets, GO terms, and KEGG pathways of Resveratrol targets and SARS-CoV-2 DEGs were confirmed. KEGG Mapper queried the location of common targets in the key pathways. A notable overlap of the GO terms and KEGG pathways between Resveratrol targets and SARS-CoV-2 DEGs was revealed. The shared targets between Resveratrol targets and SARS-CoV-2 mainly involved the IL-17 signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway. Our study uncovered that Resveratrol is a promising therapeutic candidate for COVID-19 and we also revealed the probable key targets and pathways involved. Ultimately, we bring forward new insights and encourage more studies on Resveratol to benefit COVID-19 patients. [ABSTRACT FROM AUTHOR]

Sleep-disordered breathing (SDB) is a frequent comorbidity in patients with wake-up stroke (WUS). It affects the occurrence of this disease through its interference of breathing changes and sleep quality. We aim to assess the performances of sleep-disordered breathing in WUS. A systematical search for the studies that investigated sleep-disordered breathing in WUS was done in PubMed, Web of Science, and Cochrane Library. Data were extracted by two independent investigators, and then analyzed using the Revman 5.0 software. A total of five studies with 591 patients were included in the meta-analysis. The pooling data of sleep parameters showed that patients with WUS had a higher AHI and ODI than those with non-WUS (NWUS) [AHI: SMD: 0.58 (0.05, 1.10), P = 0.03; ODI: SMD: 0.63 (0.06, 1.21), P = 0.03). In addition, an increased incidence of severe SAS is found in WUS (OR: 3.18; 95% CI 1.27, 7.93; P = 0.01). However, no differences were found in AI, ESS, and the number of sleep apnea syndrome (SAS) between the two groups (P > 0.05). Therefore, WUS patients intended to have a severe SDB status, affecting the respiratory effects. Early prevention and attention should be paid on potential stroke sufferers with SAS, especially those with severe SAS. [ABSTRACT FROM AUTHOR]

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1–42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1–42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1. [ABSTRACT FROM AUTHOR]

Analgesic overuse often happens to migraine patients, especially chronic migraineurs, and migraine has been demonstrated to be associated with white matter lesions (WMLs). The aim of this study was to investigate the relationship between medication overuse headache (MOH) and WMLs in chronic migraine (CM) patients. Subjects were enrolled and divided into three groups: healthy controls, CM without MOH (CMwoMOH), and CM with MOH (CM-MOH). Most of the CM patients used non-steroidal anti-inflammatory drugs (NSAIDs) as acute headache medications. All the participants underwent magnetic resonance imaging scans and images were obtained for WML evaluation with semiquantitative scales. One hundred and forty-one participants were included, 45 of them for controls, 38 for CMwoMOH, and 58 for CM-MOH. In women, CMwoMOH patients had a higher prevalence of high WML load compared with controls and CM-MOH patients. In men, however, all the study groups showed no differences in the prevalence of high WML load. CMwoMOH women had increased risks of high deep white matter lesion (DWML) load compared with controls, while they had no risks of high periventricular white matter lesion (PVWML) load. CM-MOH women had no risks of high DWML load, but they had reduced risks of high PVWML load. The association of CM-MOH with high WML load in women was not changed when compared with CMwoMOH. Age was independently associated with high WML load among women. These data suggest that MOH caused by NSAIDs is not a risk factor for WMLs. Rather, NSAID overuse probably protects MOH patients from WMLs through anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin can bind senile plaques and promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits. Curcumin can also reverse distorted and curvy neurites around senile plaques and repair the neuritic abnormalities. We hypothesized whether altered neurite morphologies resulting from Aβ production had anything to do with the changes of expression of microtubule-associated protein 2 (MAP2), but curcumin could reverse damaged neurites by upregulation of MAP2 expression. In present study we designed and chemically synthesized curcumin and its six derivatives. After screening the protective effect of curcumin and derivatives, we found that the viability of SK-N-SH cell model induced by Aβ1–42 was significantly increased by curcumin and Cur1, and the expression of MAP-2 protein was obviously up-regulated in immunocytochemical staining and Western blot. The cell morphologies, including the number of neurites, neurite growth and neurite extension, were significantly improved. Cur1 showed more significant protective effect on SK-N-SH cells than curcumin. Our study revealed for the first time that the neuroprotective effect of curcumin and curcumin derivatives not only directly depends on their special chemical constitution, but they can resist to Aβ damage by up-regulation of MAP-2 expression. In view of the special advantages of curcumin and Cur1, we reasonably believe that curcumin and Cur1 may be considered as an ideal therapeutic agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

To improve the drag reduction performance of underwater vehicles, a skin composed of micro floating raft arrays and a bionic compliant wall is proposed. The micro floating raft is a miniaturization of the floating raft system which is widely used in vibration and noise reduction. The drag reduction characteristics of the skin with various structural parameters are simulated with the IB2d software based on the immersed boundary method. A considerable reduction (up to 15%) in the viscous force is observed for the skin with a certain range of l*, i.e., the spacing between the micro floating raft arrays, which is resulted from the decrease of the velocity near the wall and the increase of the boundary layer thickness. Meanwhile, the drag reduction performance of the skin is also improved by increasing the porosity coefficient α* of the compliant wall, as well as the stiffness ratio γ* and the intermediate mass m* of the micro floating raft, within limits. This study provides a new idea for designing the coating of underwater vehicles and reveals the corresponding drag reduction mechanism to a certain extent. [ABSTRACT FROM AUTHOR]

Background: Brachial plexus root avulsion (BPRA), a disabling peripheral nerve injury, induces substantial motoneuron death, motor axon degeneration and denervation of biceps muscles, leading to the loss of upper limb motor function. Acetylglutamine (N-acetyl-L-glutamine, NAG) has been proven to exert neuroprotective and anti-inflammatory effects on various disorders of the nervous system. Thus, the present study mainly focused on the influence of NAG on motor and sensory recovery after BPRA in rats and the underlying mechanisms. Methods: Male adult Sprague Dawley (SD) rats were subjected to BPRA and reimplantation surgery and subsequently treated with NAG or saline. Behavioral tests were conducted to evaluate motor function recovery and the mechanical pain threshold of the affected forelimb. The morphological appearance of the spinal cord, musculocutaneous nerve, and biceps brachii was assessed by histological staining. Quantitative real-time PCR (qRT‒PCR) was used to measure the mRNA levels of remyelination and regeneration indicators in myocutaneous nerves. The protein levels of inflammatory and pyroptotic indicators in the spinal cord anterior horn were measured using Western blotting. Results: NAG significantly accelerated the recovery of motor function in the injured forelimbs, enhanced motoneuronal survival in the anterior horn of the spinal cord, inhibited the expression of proinflammatory cytokines and pyroptosis pathway factors, facilitated axonal remyelination in the myocutaneous nerve and alleviated atrophy of the biceps brachii. Additionally, NAG attenuated neuropathic pain following BPRA. Conclusion: NAG promotes functional motor recovery and alleviates neuropathic pain by enhancing motoneuronal survival and axonal remyelination and inhibiting the pyroptosis pathway after BPRA in rats, laying the foundation for the use of NAG as a novel treatment for BPRA. [ABSTRACT FROM AUTHOR]

• Overexpressing METTL3 promotes the m6A expression and the maturation of miR-124-3p. • Overexpressing METTL3 exerts anti-inflammatory and antioxidative stress effects in hyperuricemia (HUA) mice. • Overexpressing METTL3 inactivates the MyD88/NF-κB pathway and NLRP3-ASC-Caspase1 inflammasome. Recent studies have uncovered that hyperuricemia (HUA) leads to cognitive deficits, which are accompanied by neuronal damage and neuroinflammation. Here, we aim to explore the role of methyltransferase-like 3 (METTL3) in HUA-mediated neuronal apoptosis and microglial inflammation. A HUA mouse model was constructed. The spatial memory ability of the mice was assessed by the Morris water maze experiment (MWM), and neuronal apoptosis was analyzed by the TdT-mediated dUTP nick end labeling (TUNEL) assay. Besides, enzyme-linked immunosorbent assay (ELISA) was utilized to measure the contents of inflammatory factors (IL-1β, IL-6, and TNF-α) and oxidative stress markers (MDA, SOD, and CAT) in the serum of mice. In vitro , the mouse hippocampal neuron (HT22) and microglia (BV2) were treated with uric acid (UA). Flow cytometry was applied to analyze HT22 and BV2 cell apoptosis, and ELISA was conducted to observe neuroinflammation and oxidative stress. In addition, the expression of MyD88, p-NF-κB, NF-κB, NLRP3, ASC and Caspase1 was determined by Western blot. METTL3 and miR-124-3p were down-regulated, while the MyD88-NF-κB pathway was activated in the HUA mouse model. UA treatment induced neuronal apoptosis in HT22 and stimulated microglial activation in BV2. Overexpressing METTL3 alleviated HT22 neuronal apoptosis and resisted the release of inflammatory cytokines and oxidative stress mediators in BV2 cells. METTL3 repressed MyD88-NF-κB and NLRP3-ASC-Caspase1 inflammasome. In addition, METTL3 overexpression enhanced miR-124-3p expression, while METTL3 knockdown aggravated HT22 cell apoptosis and BV2 cell overactivation. METTL3 improves neuronal apoptosis and microglial activation in the HUA model by choking the MyD88/NF-κB pathway and up-regulating miR-124-3p. [ABSTRACT FROM AUTHOR]

SUMMARY: Because of their high efficiency during chromosome doubling, immature haploid maize (Zea mays L.) embryos are useful for doubled haploid production. The R1‐nj marker is commonly used in doubled haploid breeding and has improved the efficiency of haploid identification. However, its effectiveness is limited by genetic background and environmental factors. We addressed this technical challenge by developing an efficient and accurate haploid embryo identification marker through co‐expression of two transcription factor genes (ZmC1 and ZmR2) driven by the embryo–aleurone‐specific bidirectional promoter PZmBD1; these factors can activate anthocyanin biosynthesis in the embryo and aleurone layer during early seed development. We developed a new haploid inducer, Maize Anthocyanin Gene InduCer 1 (MAGIC1), by introducing the transgenes into the haploid inducer line CAU6. MAGIC1 could identify haploids at 12 days after pollination, which is nine days earlier than CAU6. Importantly, MAGIC1 increased haploid identification accuracy to 99.1%, compared with 88.3% for CAU6. In addition, MAGIC1 could effectively overcome the inhibition of anthocyanin synthesis in some germplasms. Furthermore, an upgraded anthocyanin marker was developed from ZmC1 and ZmR2 to generate MAGIC2, which could identify haploids from diploids due to differential anthocyanin accumulation in immature embryos, coleoptiles, sheaths, roots, leaves, and dry seeds. This haploid identification system is more efficient and accurate than the conventional R1‐nj‐based method, and it simplifies the haploid identification process. Therefore, this system provides technical support for large‐scale doubled haploid line production. Significance Statement In this study, we developed a powerful visualized marker by expressing ZmC1 and ZmR2 and then introduced this marker into the haploid inducer CAU6 to generate a new inducer called MAGIC1 and MAGIC2. This provides an efficient haploid identification system with higher accuracy, simple operation, and reduced work time for large‐scale applications in doubled haploid technology. [ABSTRACT FROM AUTHOR]

[Display omitted] Natural organisms have evolved sophisticated and multiscale hierarchical structures over time to enable survival. Currently, bionic design is revolutionizing drug delivery systems (DDS), drawing inspiration from the structure and properties of natural organisms that offer new possibilities to overcome the challenges of traditional drug delivery systems. Bionic drug delivery has contributed to a significant improvement in therapeutic outcomes, providing personalized regimens for patients with various diseases and enhancing both their quality of life and drug efficacy. Therefore, it is important to summarize the progress made so far and to discuss the challenges and opportunities for future development. Herein, we review the recent advances in bio-inspired materials, bio-inspired drug vehicles, and drug-loading platforms of biomimetic structures and properties, emphasizing the importance of adapting the structure and function of organisms to meet the needs of drug delivery systems. Finally, we highlight the delivery strategies of bionics in DDS to provide new perspectives and insights into the research and exploration of bionics in DDS. Hopefully, this review will provide future insights into utilizing biologically active vehicles, bio-structures, and bio-functions, leading to better clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose: Parkinson's disease (PD), a common neurodegenerative disorder with motor and nonmotor symptoms, does not have effective treatments. Dietary tryptophan (Trp) supplementation has potential benefits for the treatment of multiple disorders. However, whether additional Trp in the diet could be beneficial for PD remains to beinvestigated. In the present study, the neuroprotective role of dietary Trp on a rotenone‐induced rat model of PD was determined. Methods: The rotenone was injected to build the PD model, and then the rats were treated with Trp in the diet. And then, an open field test, western blot analysis, and enzyme linked immunosorbent assay (ELISA) were performed. Results: We observed that dietary Trp significantly ameliorated impaired motor function, upregulated tyrosine hydroxylase expression, inhibited the nuclear transport of Nuclear factor‐kappa B (NF‐κB) in substantia nigra (SN), and downregulated the protein levels of IL‐1β, IL‐6, and TNF‐α in serum in rotenone‐treated rats. However, these patterns were reversed in response to treatment with ampicillin, an agent that can clean intestinal Trp metabolism flora. Moreover, after using CH223191, an inhibitor of the aromatic hydrocarbon receptor (AhR) pathway, dietary Trp could not exert neuroprotective roles in the rotenone‐induced rat model of PD. Conclusion: These results suggest that Trp in the diet can protect against rotenone‐induced neurotoxicity to ameliorate motor deficits, which may be mediated through activating AhR pathway. [ABSTRACT FROM AUTHOR]

Background and Purpose: Enhanced remyelination of the regenerated axons results in functional re‐innervation and improved functional motor recovery after brachial plexus root avulsion (BPRA). The neural cell adhesion molecule L1 (L1CAM, L1) regulates myelination and promotes regeneration after acute injury in the nervous system. Berberine (BBR) can exert neuroprotective roles against the lesion. Herein, we investigated whether berberine (BBR) can affect the expression of L1 and enhance the axonal remyelination in rats following BPRA. Methods: The surgical procedures were performed to build the rat brachial plexus avulsion and re‐implantation model, and then, the rats were treated with BBR. After the rehabilitation for 12 weeks, the musculocutaneous nerves were collected for quantitative real‐time PCR, Western blot analysis, and histochemical and immunofluorescence staining. Results: We observed that, BBR treatment ameliorated the abnormal musculocutaneous nerve fibers morphology, up‐regulated the L1 expression, increased the myelination‐related genes, decreased the differentiated‐associated genes, and up‐regulated the phosphorylation of ERK. Conclusion: These results suggest that BBR may enhance L1 expression and promote axonal remyelination after spinal root avulsion. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disease. It can lead to progressive cognitive impairment, memory loss, and behavioral alterations. So far, the exact cellular and molecular mechanisms underlying this disorder remain unclear. And there are no effective treatments to prevent, halt, or reverse AD. In recent years, Chinese traditional medicine has become a new force in the treatment of AD, and the typical representatives of natural herbal ingredients are curcumin and its derivatives. Bisdemethoxycurcumin (BDMC), which is a classical derivative of curcumin, was found to have neuroprotective effects against a cell model of Alzheimer's disease (AD) in our previous studies. This study investigated the intrinsic mechanism of BDMC against AD in animal models. Methods: In this study, BDMC was injected into the lateral ventricles of normal C57BL/6 mice, APP/PS mice, and APP/PS mice treated with EX527 (the inhibitor of SIRT1). Y maze and Morris water maze were used to test the learning and memory ability of mice. Nissl staining was used to observe the morphological changes of neurons. Immunofluorescence staining was used to detect Aβ deposition in mice. The activities of GSH and SOD were determined to observe the levels of oxidative stress in mice. And Western blot analyses were used to detect content of SIRT1 in mice. Results: In the APP/PS mice, after BDMC intervention, their cognitive function improved, oxidative stress adjusted, the number of neurons increased, Aβ deposition decreased, and the level of SIRT1 expression increased. However, when SIRT1 is inhibited, BDMC on the improvement in the learning and memory ability and the improvement on oxidative stress in APP/PS1 mice were reversed. Conclusion: Our findings demonstrated that in the AD mice, BDMC has antagonistic effect on AD. And an intermediate step in the antagonism effect is caused by SIRT1 upregulation, which leading to decreased oxidative stress. Based on these, we concluded that BDMC injection into the lateral ventricle can act against AD by upregulating SIRT1 to antioxidative stress. [ABSTRACT FROM AUTHOR]

Background and Purpose: Radiation‐induced brain injury (RBI) usually occurs six months to three years after irradiation, often shows cognitive dysfunction, epilepsy, and other neurological dysfunction. In severe cases, it can cause a wide range of cerebral edema, even herniation. It seriously threatens the survival of patients and their quality of life, and it becomes a key factor in limiting the radiation dose and lowering the therapeutic efficacy in recent years. Therefore, studying the pathogenesis of RBI and exploring new therapeutic targets are of great significance. Methods: In our study, we observed the activation and secretory function in astrocytes as well as the intracellular signal transducer and activator of transcription 3 (STAT3) signal transduction pathway activation status after exposing different doses of X‐ray irradiation by using MTT, Immunocytologic analysis, and Western blot analysis. Further, we used the same way to explore the role of vascular endothelial growth factor (VEGF) in signal transduction pathways playing in the activation of astrocytes after irradiating through the use of specificInhivascular endothelial growth factorbitors of STAT3. Results: Ast can be directly activated, reactive hyperplasia and hypertrophy, the expression of the activation marker glial fibrillary acidic protein is increased, and the expression of vascular endothelial growth factor (VEGF) in the cells is increased, which may lead to RBI. After the addition of STAT3 pathway inhibitor, most of the Ast radiation activation was suppressed, and the expression of high‐level expression of VEGF decreased after irradiation. Conclusion: Our findings demonstrated that X‐ray irradiation directly induced the activation of astrocytes in a persistent manner and X‐ray irradiation activated STAT3 signaling pathway. As the same time, we found that X‐ray irradiation induced the activation of astrocytes and secretion cytokine. The STAT3 signaling pathway may participate in the pathogenesis of radiation‐induced brain injury. [ABSTRACT FROM AUTHOR]

Abstract: The development of efficient catalysts for both oxygen reduction and evolution reactions (oxygen reduction reaction (ORR) and oxygen evolution reaction (OER)) is central to regenerative fuel cells and rechargeable metal–air batteries. It is highly desirable to achieve the efficient integration of dual active components into the catalysts and to understand the interaction between the dual components. Here, a facile approach is demonstrated to construct defective carbon–CoP nanoparticle hybrids as bifunctional oxygen electrocatalysts, and further probe the interfacial charge distribution behavior. By combining multiple synchrotron‐based X‐ray spectroscopic characterizations with density functional theory calculations, the interfacial charge polarization with the electrons gathering at the defective carbon surface and the holes gathering at the CoP surface due to strong interfacial coupling is revealed, which simultaneously facilitates the ORR and OER with remarkable bifunctional oxygen electrode activities. This work not only offers a bifunctional oxygen catalyst with outstanding performance, but also unravels the promoting factor of the hybrids from the view of interfacial charge distribution. [ABSTRACT FROM AUTHOR]

Extensive scar tissue formation often occurs after severe burn injury, trauma, or as one of complications after surgical intervention. Despite significant therapeutic advances, it is still a significant challenge to manage massive scar tissue formation while also promoting normal wound healing. The goal of this study was to investigate the therapeutic effect of bone mesenchymal stem cells (BMSCs) that were genetically modified to overexpress transforming growth factor-beta 3 (TGF-β 3 ), an inhibitor of myofibroblast proliferation and collagen type I deposition, on full-thickness cutaneous wound healing in a rabbit model. Twenty-four rabbits with surgically-induced full-thickness cutaneous wounds created on the external ear (1.5 × 1.5 cm, two wounds/ear) were randomized into four groups: ( G1 ), wounds with no special treatment but common serum-free culture medium as negative controls; ( G2 ), topically-applied recombinant adenovirus, expressing TGF-β 3 /GFP; ( G3 ), topically-applied BMSCs alone; ( G4 ), topically-applied BMSCs transfected with Ad-TGF-β 3 /GFP (BMSCs TGF-β3 ); and (G5), an additional normal control (n = 2) with neither wound nor treatment on the external ear skin. The sizes of wounds on the ear tissues were grossly examined, and the scar depth and density of wounds were histologically evaluated 21, 45, and 90 days after surgical wound creation. Our results demonstrated that G4 significantly reduced the wound scar depth and density, compared to G1~3. Numbers of cells expressing GFP significantly increased in G4, compared to G2. The protein expression of TGF-β 3 and type III collagen in G4 significantly increased, while the ratio of type I to type III collagen was also significantly reduced, which is similar to the tissue architecture found in G5 , as compared the other treatment groups. In conclusion, transplantation of BMSCs TGF-β3 remarkably improves wound healing and reduces skin scar tissue formation in an animal model, which may potentially provide an alternative in the treatment of extensive scar tissue formation after soft tissue injury. [ABSTRACT FROM AUTHOR]

[Display omitted] • MICU3 expression is increased in brain of CAA mice. • MICU3 improves behavioral performances in CAA mice. • MICU3 reduces Aβ accumulation in CAA mice. • MICU3 improves neuronal survival in cortex and hippocampus of CAA mice. • MICU3 restrains oxidative stress in cortex and hippocampus of CAA mice. Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-β (Aβ) accumulation, and always accompanied by Alzheimer's disease (AD). Mitochondrial dysfunction-associated cellular events including cell death, inflammation and oxidative stress are implicated in the progression of CAA. Unfortunately, the molecular mechanisms revealing CAA pathogenesis are still obscure, thus requiring further studies. Mitochondrial calcium uptake 3 (MICU3), a regulator of the mitochondrial Ca2+ uniporter (MCU), mediates various biological functions, but its expression and influence on CAA are largely unknown. In the present study, we found that MICU3 expression was gradually declined in cortex and hippocampus of Tg-SwDI transgenic mice. Using stereotaxic operation with AAV9 encoding MICU3, we showed that AAV-MICU3 improved the behavioral performances and cerebral blood flow (CBF) in Tg-SwDI mice, along with markedly reduced Aβ deposition through mediating Aβ metabolism process. Importantly, we found that AAV-MICU3 remarkably improved neuronal death and mitigated glial activation and neuroinflammation in cortex and hippocampus of Tg-SwDI mice. Furthermore, excessive oxidative stress, mitochondrial impairment and dysfunction, decreased ATP and mitochondrial DNA (mtDNA) were detected in Tg-SwDI mice, while being considerably ameliorated upon MICU3 over-expression. More importantly, our in vitro experiments suggested that MICU3-attenuated neuronal death, activation of glial cells and oxidative stress were completely abrogated upon PTEN induced putative kinase 1 (PINK1) knockdown, indicating that PINK1 was required for MICU3 to perform its protective effects against CAA. Mechanistic experiment confirmed an interaction between MICU3 and PINK1. Together, these findings demonstrated that MICU3-PINK1 axis may serve as a key target for CAA treatment mainly through improving mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-β (Aβ) accumulation, and always accompanied by Alzheimer's disease (AD). The mechanisms revealing CAA pathogenesis are still unclear, and it is challenging to develop an efficient therapeutic strategy for its treatment. Vascular endothelial growth factor (VEGF) and its receptors including VEGFR-1,-2,-3 activation are involved in Aβ processing, and modulate numerous cellular events associated with central nervous system (CNS) diseases. In the present study, we attempted to explore the regulatory function of fruquintinib (also named as HMPL-013), a highly selective inhibitor of VEGFR-1,-2,-3 tyrosine kinases, on CAA progression in Tg-SwDI mice. Here, we found that HMPL-013-rich diet consumption for 12 months significantly improved the behavioral performances and cerebral blood flow (CBF) of Tg-SwDI mice compared with the vehicle group. Importantly, HMPL-013 administration considerably reduced Aβ 1-40 and Aβ 1-42 burden in cortex and hippocampus of Tg-SwDI mice through regulating Aβ metabolism process. Congo red staining confirmed Aβ deposition in vessel walls, reflecting CAA formation, which was, however, strongly ameliorated after HMPL-013 treatment. Neuron death, aberrant glial activation and pro-inflammatory response in brain tissues of Tg-SwDI mice were dramatically alleviated after HMPL-013 consumption. More studies showed that the protective effects of HMPL-013 against CAA might be partially attributed to its regulation on the expression of genes associated with blood vasculature. Intriguingly, VEGF and phosphorylated VEGFR-1,-2 protein expression levels were remarkably decreased by HMPL-013 in cortex and hippocampus of Tg-SwDI mice, which were validated in HMPL-013-treated brain vascular endothelial cells (BVECs) under hypoxia. Finally, we found that VEGF-induced human umbilical vein endothelial cells (HUVEC) proliferation and tube formation were strongly abolished upon HMPL-013 exposure. Collectively, all these findings demonstrated that oral administration of HMPL-013 had therapeutic potential against CAA by reducing Aβ deposition, inflammation and neuron death via suppressing VEGF/VEGFR-1,-2 signaling. [Display omitted] • HMPL-013 mitigates impaired behavioral performance in Tg-SwDI mice with CAA. • HMPL-013 consumption reduces Aβ accumulation in Tg-SwDI mice. • HMPL-013 ameliorates Aβ metabolism in vitro and in vivo via suppression of ROS and inflammation. • HMPL-013 improves neuron survival in Tg-SwDI mice. • HMPL-013 reduces glial cell activation in Tg-SwDI mice. [ABSTRACT FROM AUTHOR]

Amyloid β (Aβ) plays an important role in Alzheimer’s disease (AD) by inducing microglia activation. Once activated, microglial cells promote the release of reactive species and cytokines that are known to enhance immune responses in AD brain. Thus, negative regulators of microglia activation are considered as potential therapeutic candidates for AD. Curcumin, the major yellow pigment in turmeric (Curcuma longa) , is proposed for its anti-inflammatory properties. Several studies have indicated the suppressive effects of curcumin on LPS-induced microglia activation and MAPK activities. However, the effects of curcumin on Aβ-treated microglia and the possible mechanisms are still not fully understood. In the present study, we found that curcumin improved microglial viability against Aβ42 in a time- and dose-dependent manner and remarkably suppressed Aβ42-induced CD68 expression. Moreover, curcumin concentration-dependently abolished Aβ42-induced interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in mRNA and protein levels in microglia. Besides, curcumin exerted an inhibitory effect on phosphorylation of ERK1/2 and p38 in Aβ42-activated microglia. Further experiments indicated that blockage of ERK1/2 and p38 pathways reduced inflammatory cytokines production from microglia. These results show that curcumin suppresses ERK1/2 and p38 signaling, thus, attenuating inflammatory responses of brain microglia. [ABSTRACT FROM AUTHOR]

Background Triptans are a family of selective serotonin (5-HT1B/1D) receptor agonists that are widely used to treat acute migraine attacks. Their efficacy is limited by side effects and the gastrointestinal manifestations of migraine. Aim To compare the efficacy of a single intravenous administration of propacetamol, a prodrug of paracetamol (acetaminophen) with a single dose of oral rizatriptan in treating acute migraine attacks Methods Patients were selected from those who presented to the emergency room with a diagnosed migraine attack and who had not previously taken any analgesics. They were randomized into 2 groups: treatment with a single 1g IV dose of propacetamol or with a single oral dose of 5mg rizatriptan. Their Visual Analogue Scale (VAS) pain scores were assessed before and at 30, 60, and 120min after treatment. Results The patients who received the propacetamol had significantly improved VAS scores at 60min compared to the rizatriptan group. There were no significant differences in VAS scores at 30 or 120min post-treatment. Conclusion Propacetamol is either equivalent or superior in efficacy to rizatriptan for treating acute migraine attacks, while having the advantage of parenteral administration in patients whose migraines are accompanied by nausea and vomiting. [ABSTRACT FROM AUTHOR]

Abstract: Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1β and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke. [Copyright &y& Elsevier]