Protective effect of sterubin against neurochemical and behavioral impairments in rotenone-induced Parkinson's disease

This study was conducted to evaluate how sterubin affects rotenone-induced Parkinson's disease (PD) in rats. A total of 24 rats were distributed into 4 equal groups: normal saline control and rotenone control were administered saline or rotenone (ROT), respectively, orally; sterubin 10 received ROT + sterubin 10 mg/kg po; and sterubin alone was administered to the test group (10 mg/kg). Rats of the normal saline and sterubin alone groups received sunflower oil injection (sc) daily, 1 h after receiving the treatments cited above, while rats of the other groups received rotenone injection (0.5 mg/kg, sc). The treatment was continued over the course of 28 days daily. On the 29th day, catalepsy and akinesia were assessed. The rats were then euthanized, and the brain was extracted for estimation of endogenous antioxidants (MDA: malondialdehyde, GSH: reduced glutathione, CAT: catalase, SOD: superoxide dismutase), nitrative (nitrite) stress markers, neuroinflammatory cytokines, and neurotransmitter levels and their metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)). Akinesia and catatonia caused by ROT reduced the levels of endogenous antioxidants (GSH, CAT, and SOD), elevated the MDA level, and altered the levels of nitrites, neurotransmitters, and their metabolites. Sterubin restored the neurobehavioral deficits, oxidative stress, and metabolites of altered neurotransmitters caused by ROT. Results demonstrated the anti-Parkinson's activities of sterubin in ROT-treated rats.

La alteración hipotalámica en la obesidad: neuroinflamación y disfunción metabólica / The hypotalamic disturbances during obesity: neuroinflammation and metabolic dysfunction

Resumen La obesidad es considerada actualmente como un problema de salud pública global y se caracteriza por la hipertrofia e hiperplasia del tejido adiposo debido a la ingesta hipercalórica y la falta de actividad física, disfunción metabólica, inflamación sistémica crónica de bajo grado y gradualmente neuroinflamación hipotalámica. El tejido adiposo actúa como un órgano endocrino secretando adipocinas y citocinas que actúan como reguladores del metabolismo. Sin embargo, la presencia de niveles elevados de ácidos grasos libres y de moléculas inflamatorias derivadas de los adipocitos, pueden alterar la respuesta inmunitaria sistémica, generando inflamación crónica, comprometiendo la integridad de la barrera hematoencefálica y estimulando la respuesta de la glía, especialmente en regiones específicas del hipotálamo, centro de regulación de la homeostasis energética. Las células gliales hipotalámicas son importantes en la transmisión de señales inflamatorias relacionadas con la dieta, pueden modular la actividad neuronal, responder a las señales inmunológicas periféricas e iniciar una respuesta inflamatoria local y gliosis. Esta revisión se enfoca en la descripción general de la disfunción metabólica asociada a la obesidad y su participación en la alteración de la regulación hipotalámica, provocando neuroinflamación y modificaciones en la conducta alimentaria.

Abstract Nowadays, obesity is considered a worldwide rising health problem and is characterized by adipose tissue hypertrophy and hyperplasia due to hypercaloric intake and lack of physical activity, promoting the development of metabolic dysfunction, low-grade systemic chronic inflammation, and gradually hypothalamic neuroinflammation. Adipose tissue acts as an endocrine organ secreting adipokines and cytokines around peripheral organs, functioning as a master metabolism regulator. However, high levels of adipocyte-derived free fatty acids and inflammatory molecules promote impairments in systemic immune response, generate chronic inflammation, disrupt the blood-brain barrier, and stimulate glia, specifically in some hypothalamic regions, the master regulators of energetic homeostasis. Hypothalamic glial cells are essential in diet-related inflammatory signals transmission and can modulate neuronal activity, also respond to peripheral inflammatory signals and begin local inflammatory response and gliosis. This review aims to analyze obesity-related metabolic dysfunction and how it participates in the hypothalamic regulation impairments due to neuroinflammation and impairment in food intake behavior.

Effects of scutellarin on neuroinflammation in rats with traumatic brain injury by regulating cGAS/STING signaling pathway / 中国药房

OBJECTIVE To investigate the improvement effects and mechanism of scutellarin （Scu） on neuroinflammation in rats with traumatic brain injury （TBI）. METHODS The modified Feeney method was applied to construct TBI rat model. The rats were randomly grouped into TBI group，Scu low-dose group （40 mg/kg），Scu high-dose group （80 mg/kg），cyclic guanylate- adenylate synthase （cGAS） inhibitor group （cGAS inhibitor RU.521，450 μg/kg），with 24 rats in each group. Other 24 rats were included in the sham operation group. The modified neurological deficit score （mNSS） method was applied to assess the neurological function of rats； the brain water content of rats was measured by dry/wet specific gravity method； hematoxylin-eosin and TdT-mediated dUTP nick-end labeling staining were applied to observe the pathological changes and apoptosis of brain tissue in rats； the levels of interferon-β （IFN-β），CXC chemokine ligand-10 （CXCL10），tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rat brain tissue were detected by enzyme-linked immunosorbent assay； Western blot method was applied to detect the expression of cGAS/interferon gene stimulating protein （STING） signal pathway-related proteins in brain tissue of rats. RESULTS Compared with the sham operation group，the mNSS，brain water content，apoptosis rate，the contents of IFN-β，CXCL10，TNF-α and IL-6，and the relative expressions of cGAS and STING proteins in TBI group increased significantly （P＜0.05）； there were edema，bleeding and pathological damage to neurons in the brain tissue. Compared with TBI group，the above indicators and pathological changes of rats in administration groups were improved significantly （P＜0.05），and the effect of Scu was in a dose- dependent manner （P＜0.05）； however，there was no statistically obvious difference in the above indicators between the Scu high- dose group and the cGAS inhibitor group （P＞0.05）. CONCLUSIONS Scu may alleviate neuroinflammation，reduce brain tissue damage and apoptosis，and promote the recovery of neural function in TBI rats by inhibiting the activation of cGAS/STING signaling pathway.

Effects of intranasal administration of tripterygium glycoside-bearing liposomes on behavioral cognitive impairment of mice induced by central nervous system inflammation / 中国中药杂志

Tripterygium glycosides liposome(TPGL) were prepared by thin film-dispersion method, which were optimized accor-ding to their morphological structures, average particle size and encapsulation rate. The measured particle size was(137.39±2.28) nm, and the encapsulation rate was 88.33%±1.82%. The mouse model of central nervous system inflammation was established by stereotaxic injection of lipopolysaccharide(LPS). TPGL and tripterygium glycosides(TPG) were administered intranasally for 21 days. The effects of intranasal administration of TPG and TPGL on behavioral cognitive impairment of mice due to LPS-induced central ner-vous system inflammation were estimated by animal behavioral tests, hematoxylin-eosin(HE) staining of hippocampus, real-time quantitative polymerase chain reaction(RT-qPCR) and immunofluorescence. Compared with TPG, TPGL caused less damage to the nasal mucosa, olfactory bulb, liver and kidney of mice administered intranasally. The behavioral performance of treated mice was significantly improved in water maze, Y maze and nesting experiment. Neuronal cell damage was reduced, and the expression levels of inflammation and apoptosis related genes [tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), BCL2-associated X(Bax), etc.] and glial activation markers [ionized calcium binding adaptor molecule 1(IBA1) and glial fibrillary acidic protein(GFAP)] were decreased. These results indicated that liposome technique combined with nasal delivery alleviated the toxic side effects of TPG, and also significantly ameliorated the cognitive impairment of mice induced by central nervous system inflammation.

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.

Chemical constituents from leaves of Jatropha curcas / 中草药·英文版

OBJECTIVE@#To investigate the chemical constituents from the leaves of Jatropha curcas and evaluate their inhibition on lipopolysaccharide (LPS)-activated BV-2 microglia cells.@*METHODS@#The n-BuOH extract of the leaves of J. curcas was isolated by macroporous adsorption resin, silica gel, ODS, column chromatography and semi-preparative HPLC. The structures of the compounds were identified by MS, NMR, ECD, and other spectroscopic methods. In addition, anti-neuroinflammatory effects of isolated compounds were evaluated by measuring the production of nitric oxide (NO) in over-activated BV-2 cells.@*RESULTS@#Seventeen compounds, including (7R,8S)-crataegifin A-4-O-β-D-glucopyranoside ( 1), (8R,8'R)-arctigenin ( 2), arctigenin-4'-O-β-D-glucopyranoside ( 3), (-)-syringaresinol ( 4), syringaresinol-4'-O-β-D-glucopyranoside ( 5), (-)-pinoresinol ( 6), pinoresinol-4'-O-β-D-glucopyranoside ( 7), buddlenol D ( 8), (2R,3R)-dihydroquercetin ( 9), (2S,3S)-epicatechin ( 10), (2R,3S)-catechin ( 11), isovitexin ( 12), naringenin-7-O-β-D-glucopyranoside ( 13), chamaejasmin ( 14), neochamaejasmin B ( 15), isoneochamaejasmin A ( 16), and tomentin-5-O-β-D-glucopyranoside ( 17) were isolated and identified. Compounds 2, 4 and 8 significantly inhibited the release of NO in BV-2 microglia activated by LPS, with IC50 values of 18.34, 29.33 and 26.30 μmol/L, respectively.@*CONCLUSION@#Compound 1 is a novel compound, and compounds 2, 3, 8, 14- 17 are isolated from Jatropha genus for the first time. In addition, the lignans significantly inhibited NO release and the inhibitory activity was decreased after glycosylation.

Role of the Voltage-Gated Proton Channel Hv1 in Nervous Systems / 神经科学通报·英文版

Hv1 is the only voltage-gated proton-selective channel in mammalian cells. It contains a conserved voltage-sensor domain, shared by a large class of voltage-gated ion channels, but lacks a pore domain. Its primary role is to extrude protons from the cytoplasm upon pH reduction and membrane depolarization. The best-known function of Hv1 is the regulation of cytosolic pH and the nicotinamide adenine dinucleotide phosphate oxidase-dependent production of reactive oxygen species. Accumulating evidence indicates that Hv1 is expressed in nervous systems, in addition to immune cells and others. Here, we summarize the molecular properties, distribution, and physiological functions of Hv1 in the peripheral and central nervous systems. We describe the recently discovered functions of Hv1 in various neurological diseases, including brain or spinal cord injury, ischemic stroke, demyelinating diseases, and pain. We also summarize the current advances in the discovery and application of Hv1-targeted small molecules in neurological diseases. Finally, we discuss the current limitations of our understanding of Hv1 and suggest future research directions.

NLRP3 Inflammasome-Mediated Neuroinflammation and Related Mitochondrial Impairment in Parkinson's Disease / 神经科学通报·英文版

Parkinson's disease (PD) is a common neurodegenerative disorder caused by the loss of dopamine neurons in the substantia nigra and the formation of Lewy bodies, which are mainly composed of alpha-synuclein fibrils. Alpha-synuclein plays a vital role in the neuroinflammation mediated by the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in PD. A better understanding of the NLRP3 inflammasome-mediated neuroinflammation and the related mitochondrial impairment during PD progression may facilitate the development of promising therapies for PD. This review focuses on the molecular mechanisms underlying NLRP3 inflammasome activation, comprising priming and protein complex assembly, as well as the role of mitochondrial impairment and its subsequent inflammatory effects on the progression of neurodegeneration in PD. In addition, the therapeutic strategies targeting the NLRP3 inflammasome for PD treatment are discussed, including the inhibitors of NLRP3 inflammatory pathways, mitochondria-focused treatments, microRNAs, and other therapeutic compounds.

A pilot study on the effects of early use of valproate sodium on neuroinflammation after traumatic brain injury / 中国当代儿科杂志

OBJECTIVES@#To study the effect of early use of sodium valproate on neuroinflammation after traumatic brain injury (TBI).@*METHODS@#A total of 45 children who visited in Xuzhou Children's Hospital Affiliated to Xuzhou Medical University from August 2021 to August 2022 were enrolled in this prospective study, among whom 15 healthy children served as the healthy control group, and 30 children with TBI were divided into a sodium valproate treatment group and a conventional treatment group using a random number table (n=15 each). The children in the sodium valproate treatment group were given sodium valproate in addition to conventional treatment, and those in the conventional group were given an equal volume of 5% glucose solution in addition to conventional treatment. The serum concentrations of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), high-mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured in the healthy control group on the day of physical examination and in the children with TBI on days 1, 3, and 5 after admission. Glasgow Outcome Scale-Extended (GOS-E) score was evaluated for the children with TBI 2 months after discharge.@*RESULTS@#Compared with the healthy control group, the children with TBI had significantly higher serum concentrations of NLRP3, HMGB1, TNF-α, and IL-1β on day 1 after admission (P<0.017). The concentration of NLRP3 on day 5 after admission was significantly higher than that on days 1 and 3 after admission in the children with TBI (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of NLRP3 than the conventional treatment group (P<0.05). For the conventional treatment group, there was no significant difference in the concentration of HMGB1 on days 1, 3, and 5 after admission (P>0.017), while for the sodium valproate treatment group, the concentration of HMGB1 on day 5 after admission was significantly lower than that on days 1 and 3 after admission (P<0.017). On day 5 after admission, the sodium valproate treatment group had a significantly lower concentration of HMGB1 than the conventional treatment group (P<0.05). For the children with TBI, the concentration of TNF-α on day 1 after admission was significantly lower than that on days 3 and 5 after admission (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of TNF-α than the conventional treatment group (P<0.05). The concentration of IL-1β on day 3 after admission was significantly lower than that on days 1 and 5 after admission (P<0.017) in the children with TBI. On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of IL-1β than the conventional treatment group (P<0.05). The GOS-E score was significantly higher in the sodium valproate treatment group than that in the conventional treatment group 2 months after discharge (P<0.05).@*CONCLUSIONS@#Early use of sodium valproate can reduce the release of neuroinflammatory factors and improve the prognosis of children with TBI.

Effect of Erjing Pills on alleviating neuroinflammation of AD rats based on TLR4/NF-κB/NLRP3 pathway and its mechanism / 中国中药杂志

This paper aimed to study the effect of Erjing Pills on the improvement of neuroinflammation of rats with Alzheimer's di-sease(AD) induced by the combination of D-galactose and Aβ_(25-35) and its mechanism. SD rats were randomly divided into a sham group, a model control group, a positive drug group(donepezil, 1 mg·kg~(-1)), an Erjing Pills high-dose group(9.0 g·kg~(-1)), and an Erjing Pills low-dose group(4.5 g·kg~(-1)), with 14 rats each group. To establish the rat model of AD, Erjing Pills were intragastrically administrated to rats for 5 weeks after 2 weeks of D-galactose injection. D-galactose was intraperitoneally injected into rats for 3 weeks, and then Aβ_(25-35) was injected into the bilateral hippocampus. The new object recognition test was used to evaluate the learning and memory ability of rats after 4 weeks of intragastric administration. Tissues were acquired 24 h after the last administration. The immunofluorescence method was used to detect the activation of microglia in the brain tissue of rats. The positive expressions of Aβ_(1-42) and phosphory protein Tau~(404)(p-Tau~(404)) in the CA1 area of the hippocampus were detected by immunohistochemistry. The levels of inflammatory factors interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) in the brain tissue were determined by enzyme-linked immunosorbent assay(ELISA). Toll-like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)/nucleotide-binding oligomerization domain-like receptors 3(NLRP3) pathway-associated proteins in the brain tissue were determined by Western blot. The results showed that as compared with the sham group, the new object recognition index of rats in the model control group decreased significantly, the deposition of Aβ_(1-42) and p-Tau~(404) positive protein in the hippocampus increased significantly, and the levels of microglia activation increased significantly in the dentate gyrus. The levels of IL-1β, TNF-α, and IL-6 in the hippocampus of the model control group increased significantly, and the expression levels of TLR4, p-NF-κB p65/NF-κB p65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus increased significantly. Compared with the model control group, the Erjing Pill groups enhanced the new object recognition index of rats, decreased the deposition of Aβ_(1-42) and the expression of p-Tau~(404) positive protein in the hippocampus, inhibited the activation of microglia in the dentate gyrus, reduced the levels of inflammatory factors IL-1β, TNF-α, and IL-6 in the hippocampus, and down-regulated the expression levels of TLR4, p-NF-κB P65/NF-κB P65, p-IκBα/IκBα, and NLRP3 proteins in the hippocampus. In conclusion, Erjing Pills can improve the learning and memory ability of the rat model of AD presumably by improving the activation of microglia, reducing the expression levels of neuroinflammatory factors IL-1β, TNF-α, and IL-6, inhibiting the TLR4/NF-κB/NLRP3 neuroinflammation pathway, and decreasing hippocampal deposition of Aβ and expression of p-Tau, thereby restoring the hippocampal morphological structure.

Anti-depression targets and mechanism study of Kaixin San / 中国中药杂志

This study identified the anti-depression targets of Kaixin San(KXS) in the brain tissue with "target fishing" strategy, and explored the target-associated pharmacological signaling pathways to reveal the anti-depression molecular mechanism of KXS. The Balb/c mouse model of depression was established by chronic unpredictable mild stress(CUMS) and the anti-depression effect of KXS was evaluated by forced swimming test and sucrose preference test. KXS active components were bonded to the benzophenone-modified magnetic nanoparticles by photocrosslinking reaction for capturing target proteins from cortex, thalamus and hippocampus of depressive mice. The target proteins were identified by liquid chromatography-mass spectrometry/mass spectrometry(LC-MS/MS). The enrichment analysis on signaling pathways was performed by Cytoscape. The potential biological functions of targets were verified by immunohistochemistry and Western blot assay. The results showed that KXS significantly improved the behavioral indexes. There were 64, 91, and 44 potential targets of KXS identified in cortex, thalamus, and hippocampus, respectively, according to the target identification experiment. The functions of these targets were mainly associated with vasopressin-regulated water reabsorption, salmonella infection, thyroid hormone synthesis, and other signaling pathways. Besides, the results of immunohistochemistry and Western blot showed that KXS up-regulated the expressions of argipressine(AVP) in the cortex, heat shock protein 60(HSP60), cytochrome C oxidase 4(COX4), and thyrotropin-releasing hormone(TRH) in the thalamus, and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and nuclear factor kappa B(NF-κB) p65 in the thalamus. Therefore, KXS may exert anti-depression effect through regulating vasopressin signaling pathway in the cortex and inflammation, energy metabolism, and thyroid hormone signaling pathways in the thalamus, and the effect of KXS on hippocampus is not significant.

Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine / 中国中药杂志

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid β(Aβ)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

In vitro immunogenic profile of recombinant SARS-CoV2 S1-RBD peptide in murine macrophage and microglial cells

BACKGROUND The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can infect common mice inducing significant pathological lung lesions and inflammatory responses. This substantially mimics coronavirus disease 19 (COVID-19) infection and pathogenesis in humans. OBJECTIVES To characterise the effects of recombinant SARS-CoV-2 S1 receptor-binding domain (RBD) peptide in murine macrophage and microglial cells' immune activation compared with classical PAMPs in vitro. METHODS Murine RAW 264.7 macrophages and BV2 microglial cells were exposed to increasing concentrations of the RBD peptide (0.01, 0.05, and 0.1 µg/mL), Lipopolysaccharide (LPS) and Poly(I:C) and evaluated after two and 24 h for significant markers of macrophage activation. We determined the effects of RBD peptide on cell viability, cleaved caspase 3 expressions, and nuclear morphometry analysis. FINDINGS In RAW cells, RBD peptide was cytotoxic, but not for BV2 cells. RAW cells presented increased arginase activity and IL-10 production; however, BV2 cells expressed iNOS and IL-6 after RBD peptide exposure. In addition, RAW cells increased cleaved-caspase-3, apoptosis, and mitotic catastrophe after RBD peptide stimulation but not BV2 cells. CONCLUSION RBD peptide exposure has different effects depending on the cell line, exposure time, and concentration. This study brings new evidence about the immunogenic profile of RBD in macrophage and microglial cells, advancing the understanding of SARS-Cov2 immuno- and neuropathology.

Oxidative stress and inflammatory process in borderline personality disorder (BPD): a narrative review

Borderline personality disorder (BPD) is a severe psychiatric condition that affects up to 2.7% of the population and is highly linked to functional impairment and suicide. Despite its severity, there is a lack of knowledge about its pathophysiology. Studies show genetic influence and childhood violence as factors that may contribute to the development of BPD; however, the involvement of neuroinflammation in BPD remains poorly investigated. This article aimed to explore the pathophysiology of BPD according to the levels of brain-derived neurotrophic factor (BDNF), inflammatory cytokines, and oxidative stress substances that exacerbate neuronal damage. Few articles have been published on this theme. They show that patients with BPD have a lower level of BDNF and a higher level of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in peripheral blood, associated with increased plasma levels of oxidative stress markers, such as malondialdehyde and 8-hydroxy-2-deoxyguanosine. Therefore, more research on the topic is needed, mainly with a pre-clinical and clinical focus.

Myeloperoxidase as a biomarker for intestinal-brain axis dysfunction induced by malnutrition and Cryptosporidium infection in weanling mice

Abstract Cryptosporidiosis is a waterborne protozoal infection that may cause life-threatening diarrhea in undernourished children living in unsanitary environments. The aim of this study is to identify new biomarkers that may be related to gut-brain axis dysfunction in children suffering from the malnutrition/infection vicious cycle is necessary for better intervention strategies. Myeloperoxidase (MPO) is a well-known neutrophil-related tissue factor released during enteropathy that could drive gut-derived brain inflammation. We utilized a model of environmental enteropathy in C57BL/6 weanling mice challenged by Cryptosporidium and undernutrition. Mice were fed a 2%-Protein Diet (dPD) for eight days and orally infected with 107-C. parvum oocysts. C. parvum oocyst shedding was assessed from fecal and ileal-extracted genomic DNA by qRT-PCR. Ileal histopathology scores were assessed for intestinal inflammation. Prefrontal cortex samples were snap-frozen for MPO ELISA assay and NF-kb immunostaining. Blood samples were drawn by cardiac puncture after anesthesia and sera were obtained for serum amyloid A (SAA) and MPO analysis. Brain samples were also obtained for Iba-1 prefrontal cortex immunostaining. C. parvum-infected mice showed sustained stool oocyst shedding for six days post-infection and increased fecal MPO and inflammation scores. dPD and cryptosporidiosis led to impaired growth and weight gain. C. parvum-infected dPD mice showed increased serum MPO and serum amyloid A (SAA) levels, markers of systemic inflammation. dPD-infected mice showed greater MPO, NF-kB expression, and Iba-1 immunolabeling in the prefrontal cortex, an important brain region involved in executive function. Our findings suggest MPO as a potential biomarker for intestinal-brain axis dysfunction due to environmental enteropathy.

Improvement effects and mechanism of total flavonoids of Bidens pilosa on lipopolysaccharide-induced neuroin-flammation in mice / 中国药房

OBJECTIVE To investigate the effect and mechanism of total flavonoids of Bidens pilosa L. （TFB） on lipopolysaccharide （LPS）-induced neuroinflammation in mice. METHODS Fifty C57BL/6 mice were randomly divided into normal control group， LPS group and TFB low-dose， medium-dose and high-dose groups， with 10 mice in each group. TFB low-dose， medium-dose and high-dose groups were given TFB solution intragastrically at 60， 120 and 240 mg/kg， and the normal control group and LPS group were given corresponding volume of normal saline， once a day， for consecutive 21 d. From the 15th day of administration， except for the normal control group， other groups were given LPS （400 μg/kg） intraperitoneally for 7 consecutive days to establish neuroinflammatory model. Brain tissues were taken under anesthesia 4 h after the final administration. The morphological changes of neuronal cells in mice were observed； the contents of nitric oxide （NO）， tumor necrosis factor α （TNF- α）， interleukin-1β （IL-1β）， IL-6 and IL-10 were measured， and the expressions of inflammatory pathway-related proteins [inducible NO synthase （iNOS）， cyclooxygenase-2 （COX-2）， myeloid differentiation factor 88 （Myd88） and protein kinase C （PKC）] were measured in the brain tissues of mice. RESULTS Compared with the normal control group， the neuronal arrangement in the hippocampal region of the brain tissue of mice in the LPS group was sparsely disorganized， with a large number of neuronal fixations and shrunken nuclei； the contents of TNF-α， IL-1β， IL-6 and NO in the brain tissue were significantly increased， the contents of IL-10 were significantly decreased， and the relative expressions of iNOS， COX-2， Myd88 and PKC proteins were significantly increased （P＜0.05）. Compared with the LPS group， the neuronal pathological changes in the brain tissue of mice in the TFB low-dose， medium-dose and high-dose groups were 202014810） significantly improved， and the changes of the above indices in the brain tissue were significantly reversed （P＜0.05） CONCLUSIONS TFB has an inhibitory effect on E-mail：pangxjun@163.com neuroinflammation， and its mechanism of action may be related to down-regulation of the expressions of inflammatory pathway-related proteins iNOS， COX-2， Myd88 and PKC， and reduction of inflammatory factors release.

Expression and role of STING-TBK1-IRF3 signaling pathway in the brain of mice with chronic stress / 西安交通大学学报(医学版)

【Objective】 To explore the expression and role of stimulator of interferon gene (STING)-TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling pathway in the brain of chronic stress mice. 【Methods】 Mice were divided into control (CON) group and chronic restraint stress (RST) group. Mice in the RST group were given chronic restraint stress stimulation (6 hours per day, 14 days). After 14 days, the mRNA expressions of pro-inflammatory cytokines CCL2, CXCL10, IL-1β, IL-6, IL-10, and TNFα in the brain were detected and analyzed by qRT-PCR; protein expression of STING, TBK1, p-TBK1, IRF3, and p-IRF3 were detected and analyzed by immunofluorescence staining and Western blotting. 【Results】 Compared to the CON group, the mRNA expressions of pro-inflammatory cytokines in the RST group were significantly increased (P<0.05). STING and microglia marker Iba-1 were highly co-located and the expression of STING was decreased as detected by immunofluorescence staining. Moreover, the protein expressions of STING, p-TBK1, and p-IRF3 were significantly decreased (all P<0.01). 【Conclusion】 Chronic restraint stress triggers a neuroinflammatory response and the STING-TBK1-IRF3 pathway in the brain of the RST mice is significantly inhibited.

Protective effect of platelet-rich plasma on LPS-induced neuroinflammation in BV2 microglia through NRF2/HO-1 pathway / 中国输血杂志

【Objective】 To investigate the protective effect and mechanism of platelet-rich plasma (PRP) on lipopolysaccharide (LPS) -induced inflammatory response in BV2 cells. 【Methods】 BV2 microglia were divided into normal control group, 10%PRP control group, LPS group (LPS induction), 3%PRP+ LPS group (LPS induction, 3%PRP pretreatment), 5%PRP+ LPS group (LPS induction, 5%PRP pretreatment), 10%PRP+ LPS group (LPS induction, 10%PRP pretreatment), and the proliferation of BV2 cells was measured by CCK-8. The mitochondrial membrane potential of BV2 cells was measured by confocal microscopy, ROS was measured by fluorescence method, and NO was measured by Griess method. The protein expressions of IL-6, TNF-α, BACH1, GPX4, NRF2 and HO-1 were detected by Western blot. In addition, BV2 microglia were treated with HO-1 inhibitor and divided into normal control group, LPS group, ZnPP+ LPS group, 10%PRP+ LPS group, ZnPP+ LPS+ 10%PRP group, and the protein expressions of HO-1, IL-6 and TNF-α were detected by Western blot. 【Results】 Compared with normal control group, PRP promoted the proliferation of BV2 cells (P<0.01). The mitochondrial membrane potential decreased, ROS production increased, the levels of NO, IL-6, TNF-α and BACH1 increased (P<0.01). However, the expression levels of GPX4, NRF2 and HO-1 decreased (P<0.01) in LPS group. Compared with LPS group, the proliferation activity and mitochondrial membrane potential of BV2 cells in 3%PRP+ LPS, 5%PRP+ LPS and 10%PRP+ LPS groups significantly increased. The levels of ROS, NO, IL-6, TNF-α and BACH1 significantly decreased (P<0.01). The expressions of GPX4, NRF2 and HO-1 in different concentrations of PRP (3%, 5% and 10%) increased (P<0.01). Moreover, the expression of IL-6 and TNF-α in ZnPP+ LPS group was significantly higher than that in LPS group after HO-1 inhibitor treatment. Compared with 10%PRP+ LPS+ ZnPP group, HO-1 inhibitor could reverse the effect of PRP on the expression of IL-6 and TNF-α in LPS-induced BV2 cells (P<0.01). 【Conclusion】 PRP inhibits the inflammatory response of BV2 microglia induced by LPS by activating the NRF2/HO-1 signaling pathway.

Neuroprotective and mechanistic study of GJ-4 on okadaic acid-induced memory impairment in mice / 药学学报

GJ-4 is crocin enrichments extracted from Gardenia jasminoides J. Ellis, and our previous studies have shown that GJ-4 significantly improved learning and memory impairment induced by Aβ in mice. Herein, a memory deficit model was developed by injecting okadaic acid (OA) into the lateral ventricle of mice, and the neuroprotection and underlying mechanism of GJ-4 on neuronal injury caused by Tau hyperphosphorylation were investigated. The Animal Care & Welfare Committee, Institute of Materia Medica, CAMS & PUMC has approved all procedures (No.00000318). GJ-4 at different doses was intragastric administration to mice for 16 days. Step-down test and Morris water maze test showed that GJ-4 could significantly improve OA-induced memory impairment in mice, and reduced the loss of Nissl bodies in the hippocampus of mice. GJ-4 could also decrease the phosphorylation level of Tau protein at Ser396, Thr231 and Ser404 via increasing protein phosphatase 2A (PP2A) activity and inhibiting glycogen synthase kinase-3β (GSK-3β) activity. Besides, further researches indicated that GJ-4 could inhibit the level of oxidative stress in the brain of OA mice, reduce neuronal apoptosis and inhibit the neuroinflammation mediated by activation of astrocytes in the hippocampus of mice, and eventually achieve its effects in improving learning and memory impairment in mice. According to these findings, we anticipated that GJ-4 might be a potential therapeutic drug for Alzheimer's disease.

Mechanism of Bugansan Decoction in ameliorating learning and memory impairment in D-galactose-induced aging rats based on AGEs/RAGE/NF-κB pathway / 数字中医药（英文）

@#Objective To investigate the underlying mechanism of the compound Bugansan Decoction (补肝散, BGSD) in intervening learning and memory in D-galactose (D-gal)-induced aging rats. @*Methods@#A total of 40 rats were randomly assigned to four groups: control, model, BGSD [14.06 g/(kg·d)], and piracetam [0.4 g/(kg·d)] groups, with 10 rats in each group. D-gal [400 mg/(kg·d)] was injected intraperitoneally to establish the aging rat model. The rats' body weight, water intake, food intake, and gripping strength were recorded each week. The eightarm maze and step-down test were used to measure the rats' capacity for learning and memory. Liver, thymus, spleen, and brain tissues were weighed to calculate the corresponding organ indices; serum malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured. Hematoxylin and eosin (HE) staining was adopted to observe the pathological changes of the hippocampus; enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the hippocampus. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of receptors for advanced glycation end products (RAGE), nuclear factor-κB (NF-κB), TNF-α, IL-6, and IL-1β mRNA in the hippocampus. Western blot (WB) was employed to detect the expression levels of advanced glycation end products (AGEs), RAGE, and NF-κB protein in the hippocampus. @*Results@#In D-gal-induced aging rats, BGSD significantly increased food intake, water intake, body weight, gripping strength, and organ indices (P < 0.05), and significantly decreased working memory error (WME), reference memory error (RME), and total memory errors (TE) in an eight-arm maze (P < 0.05). In the step-down test, step-down latency was prolonged and the frequency of errors dropped (P < 0.05). Additionally, BGSD could lessen the harm done to hippocampus neurons, increase serum SOD activity, lower MDA levels, and down-regulate the expression levels of the pro-inflammatory molecules TNF-α, IL-6, and IL-1β (P < 0.05). Further findings showed that BGSD significantly decreased hippocampal AGEs, RAGE, and NF-κB expression (P < 0.05). @*Conclusion@#By blocking the AGEs/RAGE/NF-κB signaling pathway, BGSD may regulate the neuroinflammatory damage in D-gal-induced aging rats, and thus improve learning and memory.