Combination therapy for pediatric patients with Kasabach-Merritt phenomenon: A single-center retrospective study.

This study aimed to in the management of Kasabach-Merritt phenomenon (KMP), a severe thrombocytopenic coagulopathy that occurs in the presence of an enlarging vascular tumor. Here, we retrospectively evaluated 12 patients with KMP in Guangzhou Women and Children's Medical Center, Guangzhou Medical University, from 2017 to 2021. 12 patients, including 7 females and 5 males, were identified. Tumors were located in the leg (n = 4), neck (n = 1), face (n = 3), chest wall (n = 1), back (n = 2), and retroperitoneum (n = 1). A plaque-like lesion with ecchymosis was the most common cutaneous manifestation. All the patients underwent embolization therapy. Nine patients received steroid treatment and 7 patients were administered with sirolimus. The mean duration of treatment was 1.6 months. All the patients reported in this study were alive when discharged. Embolization combined with steroid and sirolimus appears effective in patients with KMP, as well as in those who experienced disease recurrence. However, a long-term follow-up of the children cured of KMP will be necessary to monitor its recurrence and improve the outcome.

Identification of the Hub Genes and the Signaling Pathways in Human iPSC-Cardiomyocytes Infected by SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) is an enveloped single-stranded RNA virus that can lead to respiratory symptoms and damage many organs such as heart, kidney, intestine, brain and liver. It has not been clearly documented whether myocardial injury is caused by direct infection of cardiomyocytes, lung injury, or other unknown mechanisms. The gene expression profile of GSE150392 was obtained from the Gene Expression Omnibus (GEO) database. The processing of high-throughput sequencing data and the screening of differentially expressed genes (DEGs) were implemented by R software. The R software was employed to analyze the Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The protein-protein interaction (PPI) network of the DEGs was constructed by the STRING website. The Cytoscape software was applied for the visualization of PPI network and the identification of hub genes. The statistical analysis was performed by the GraphPad Prism software to verify the hub genes. A total of 516 up-regulated genes and 191 down-regulated genes were screened out. The top 1 enrichment items of GO in biological process (BP), Cellular Component (CC), and Molecular Function (MF) were type I interferon signaling pathway, sarcomere, and receptor ligand activity, respectively. The top 10 enrichment pathways, including TNF signaling pathway, were identified by KEGG enrichment analysis. A PPI network was established, consisting of 613 nodes and 3,993 edges. The 12 hub genes were confirmed as statistically significant, which was verified by GSE151879 dataset. In conclusion, the hub genes of human iPSC-cardiomyocytes infected with SARS-CoV-2 were identified through bioinformatics analysis, which may be used as biomarkers for further research.

Gallic Acid Induces Neural Stem Cell Differentiation into Neurons and Proliferation through the MAPK/ERK Pathway.

Neural stem cell (NSC) differentiation and proliferation are important biological processes in the cerebral neural network. However, these two abilities of NSCs are limited. Thus, the induction of differentiation and/or proliferation through the administration of plant-derived small-molecule compounds could be used to repair damaged neural networks. The present study reported that gallic acid (GA), an important phenolic acid found in tea, selectively caused NSCs to differentiate into immature neurons and promoted NSC proliferation by activating the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway. In addition, it was found that 3,4-dihydroxybenzoic acid was the main active structure exhibiting neurotrophic activity. The substitution of the carboxyl group on the benzene ring with the ester group may promote differentiation based on the structure of 3,4-dihydroxybenzoic acid. Furthermore, the introduction of the 5-hydroxyl group may promote proliferation. The present study identified that GA can promote the differentiation and proliferation of NSCs in vitro and exert pharmacological activity on NSCs.

Identification of potential biomarkers in dengue via integrated bioinformatic analysis.

Dengue fever virus (DENV) is a global health threat that is becoming increasingly critical. However, the pathogenesis of dengue has not yet been fully elucidated. In this study, we employed bioinformatics analysis to identify potential biomarkers related to dengue fever and clarify their underlying mechanisms. The results showed that there were 668, 1901, and 8283 differentially expressed genes between the dengue-infected samples and normal samples in the GSE28405, GSE38246, and GSE51808 datasets, respectively. Through overlapping, a total of 69 differentially expressed genes (DEGs) were identified, of which 51 were upregulated and 18 were downregulated. We identified twelve hub genes, including MX1, IFI44L, IFI44, IFI27, ISG15, STAT1, IFI35, OAS3, OAS2, OAS1, IFI6, and USP18. Except for IFI44 and STAT1, the others were statistically significant after validation. We predicted the related microRNAs (miRNAs) of these 12 target genes through the database miRTarBase, and finally obtained one important miRNA: has-mir-146a-5p. In addition, gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out, and a protein-protein interaction (PPI) network was constructed to gain insight into the actions of DEGs. In conclusion, our study displayed the effectiveness of bioinformatics analysis methods in screening potential pathogenic genes in dengue fever and their underlying mechanisms. Further, we successfully predicted IFI44L and IFI6, as potential biomarkers with DENV infection, providing promising targets for the treatment of dengue fever to a certain extent.

P38 MAPK/AKT signalling is involved in IL-33-mediated anti-apoptosis in childhood acute lymphoblastic leukaemia blast cells.

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is often characterized by broad clinical and biological heterogeneity, as well as recurrent genetic aberrations. Despite remarkable improvements in the treatment outcome in paediatric ALL over the past several decades, it remains a leading cause of morbidity and mortality among children. Cytokines have been extensively studied in haematologic diseases; however, the mechanisms by which cytokines contribute to ALL pathogenesis remain poorly understood. METHODS: IL-33 levels were measured by enzyme-linked immunosorbent assay (ELISA). IL1RL1 expression on ALL cell surface was accessed by flow cytometry. Expression of phosphorylated p38 MAPK, p38, pAKT, AKT and GAPDH were quantified by western blot. Cell survival signals were evaluated by apoptosis using flow cytometry. RESULTS: BM samples from ALL patients at diagnosis upregulated their cell surface expression of IL1RL1, and a higher interleukin (IL)-33 level in the serum was observed as compared to the healthy individuals. Moreover, exogenous IL-33 treatment significantly inhibited apoptosis by activating p38 mitogen-activated protein kinase (MAPK) and AKT pathway, while the inhibitor for p38 MAPK, SB203580, counteracted IL-33-induced anti-apoptosis via inactivation of p38 MAPK and AKT. Furthermore, IL-33 negatively regulates cyclin B1 protein level while increasing the expression of CDK1, with SB203580 inhibiting the effect. CONCLUSION: Our study reveals an important role for IL-33/IL1RL1 axis in supporting ALL which may represent a novel treatment for paediatric patients.KEY MESSAGESBoth IL-33 and IL1RL1 levels are upregulated in primary ALL samples.IL-33 increased both p38 MAPK and AKT activation in ALL.IL-33 promotes survival and cell cycle progression of ALL cells via activating p38 MAPK.

IL-33/IL1RL1 axis regulates cell survival through the p38 MAPK pathway in acute myeloid leukemia.

Acute myeloid leukemia (AML) is often characterized by the presence of specific and recurrent chromosomal abnormalities. Current treatments have greatly increased remission rate, but relapse still occurs. Therefore, novel therapeutic approaches are required. Previously, using a conditional Cbfb-MYH11 knockin mouse model, we showed that Cbfb-MYH11 induces the expression of a cytokine receptor, IL1RL1. Treatment with IL-33, the only known ligand of IL1RL1, promotes leukemia cell survival in vitro. We further found that IL1RL1+ cells survive better with chemotherapy than IL1RL1- population. However, the mechanism is not clear. Here, we show that IL-33 treatment decreased drug sensitivity in the human inv(16) AML cell line ME-1. By RT-PCR, we found that IL-33 increased the expression of IL-4 and IL-6 and led to the activation of both p38 MAPK and NF-κB. We also showed that IL-33 decreased apoptosis with increased phosphorylation of p38 MAPK. Moreover, pre-treatment with MAPK inhibitor attenuated the phosphorylation of p38 enhanced by IL-33 and reversed the anti-apoptotic effect by IL-33. Taken together, our findings give news insights into the potential mechanism of the anti-apoptotic effect by IL-33/IL1RL1 axis in AML which will help in future drug development.

Wogonoside inhibits inflammatory cytokine production in lipopolysaccharide-stimulated macrophage by suppressing the activation of the JNK/c-Jun signaling pathway.

BACKGROUND: Mediated by innate immune cells, inflammation is an underlying presence in the pathogenesis of numerous pulmonary diseases. Macrophages play a critical role in mediating the initial response to infection in the lungs. When there is excessive activation of macrophages, hyper-production of inflammatory factors occurs, with inflammation as the ultimate result. Wogonoside, a bioactive flavonoid glycoside, has been reported to alleviate pulmonary inflammation. However, the mechanism underlying the anti-inflammatory effect of wogonoside has not yet been clarified. METHODS: The productions of nitric oxide (NO) and reactive oxygen species (ROS) were determined using a Griess reagent kit and a DAF-FM DA fluorescent probe, respectively. Moreover, the mRNA levels of inflammatory factors were quantified by qPCR, and the binding ability of c-Jun to promoters of inflammatory factors was performed by ChIP assay. Western blot was employed to detect the protein expression of inflammatory factors and signaling pathway. RESULTS: In this study, we found that pre-treatment with wogonoside dramatically suppressed lipopolysaccharide (LPS)-induced increase in the protein and mRNA levels of inflammatory factors in macrophages, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6. Furthermore, wogonoside profoundly reduced the increase in NO and ROS production and significantly blocked phosphorylation of JNK in LPS-stimulated macrophages. As revealed by Western blot and qPCR analysis, wogonoside mediated the JNK-dependent inhibitory effect. Compared with wogonoside alone, a combination of wogonoside and JNK inhibitor SP600125 provided no extra benefit in suppressing the protein expression and mRNA levels of inflammatory factors in LPS-stimulated macrophages. Additionally, ChIP analysis demonstrated wogonoside to remarkably reduce c-Jun enrichment in COX-2, iNOS, IL-1ß, TNF-α, and IL-6 promoters. CONCLUSIONS: Collectively, our findings showed that wogonoside notably suppresses LPS-stimulated production of inflammatory factors by repressing the activation of the JNK/c-Jun signaling pathway in macrophages. This suggests that wogonoside could serve as a promising therapeutic agent for pulmonary diseases related to macrophage inflammation.

Huang-Qi San improves glucose and lipid metabolism and exerts protective effects against hepatic steatosis in high fat diet-fed rats.

Numerous researches supported that non-alcoholic fatty liver disease (NAFLD) was an emerging problem associated with increased visceral adiposity (obesity), diabetes and related metabolic disorders. Huang-Qi San (HQS) is composed of three traditional Chinese medicines (Astragali Radix, Pueraria Radix and Cortex Mori Radicis) with a weight ratio of 1:2:1. HQS has been reported to be effective in improving glucose-lipid metabolism, but its underlying mechanism on NAFLD has not been fully understood. The purpose of the present study was to assess the protective effects of HQS on obesity-induced hepatic steatosis in rats fed with high fat diet (HFD). Our data revealed that administration of HQS (1.2 and 2.4 g/kg body weight) resulted in significant reduction in body weight (BW) and organs coefficients of visceral fat. The full-Body CT scan demonstrated that HQS reduced liver fat ratio, visceral and subcutaneous fat mass in a dose-dependent manner. Additionally, HQS decreased plasma TC, TG, FFA and FABP4 levels, normalized glucose and insulin levels, and improved the glucose tolerance. Pathological examination showed that HQS alleviated hepatic steatosis and reduced the cell size of epididymal visceral adipose tissue. Hepatic lipid accumulation was also reduced by HQS treatment compared with HFD fed rats. RNA-Seq analysis combining with qPCR demonstrated that the mRNA expression of some important glucose and lipid metabolism-related genes including Acat2, Apoc4, Bhmt, Cyp3a62, Cyp51, Egln3 (Phd3), Fads1, Fads2, Gnmt, Hmgcs1 and Pemt, were significantly changed by HQS treatment. Taken together, these results suggested that HQS had beneficial effects on glucose-lipid metabolism and hepatic steatosis, and its mechanism might be related to the functions of the genes in regulating glucose and lipid metabolism.

The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice.

Although lipopolysaccharides (LPS) have been used to establish animal models of memory loss akin to what is observed in Alzheimer's disease (AD), the exact mechanisms involved have not been substantiated. In this study, we established an animal model of learning and memory impairment induced by LPS and explored the biological processes and pathways involved. Mice were continuously intraperitoneally injected with LPS for 7 days. Learning- and memory-related behavioral performance and the pathological processes involved were assessed using the Morris water maze test and immunostaining, respectively. We detected comprehensive expression of C1q, C3, microglia, and their regulatory cytokines in the hippocampus. After 7 days of LPS administration, we were able to observe LPS-induced learning and memory impairment in the mice, which was attributed to neural impairment and synapse loss in the hippocampus. We elucidated that the immune system was activated, with the classical complement pathway and microglial phagocytosis being involved in the synapse loss. This study demonstrates that an LPS-injected mouse can serve as an early memory impairment model for studies on anti-AD drugs.

Methyl 3,4-dihydroxybenzoate protects retina in a mouse model of acute ocular hypertension through multiple pathways.

Methyl 3,4 dihydroxybenzoate (MDHB) is a small molecule that shows neuroprotective effects in vitro and in a photoreceptor-degenerative mouse model. Here we investigated whether MDHB protects retina in a mouse model of acute ocular hypertension (AOH) and explores the underlying mechanisms. AOH was induced in mice by increasing intraocular pressure to approximately 90 mmHg for 60 min, then MDHB or vehicle was intraperitoneally injected daily up to 7 days. Immunostaining and multi-electrode array recordings were performed to examine the structure and function of retinas receiving the treatments. Western-blotting was applied to test the expression of several proteins related to oxidative stress and brain-derived neurotrophic factor (BDNF)-initiated signaling. Results showed that AOH injury reduced the number of Brn3a-stained retinal ganglion cells (RGCs) and ChAT-amacrine cells; thinned the inner retinal layers and induced apoptosis. Physiologically, AOH decreased the response of OFF and ON-OFF RGCs. All of these changes were reversed by MDHB-treatment. Mechanistically, MDHB appeared to work on three parallel pathways: (1) MDHB decreased the production of reactive oxygen species, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and cytosol heme oxygenase 1 (HO-1); (2) It upregulated the expression of BDNF and its receptor tropomyosin-related kinase B (TrkB), and activated the downstream AKT pathways; (3) It inhibited reactive gliosis by reducing GFAP and Iba-1 expression. Thus our results suggest that MDHB protects retina against AOH injury by inhibiting oxidative stress, activating the BDNF/AKT signaling and inhibiting inflammatory pathways. Therefore, MDHB may serve as a promising candidate to treat retinal ischemia.

Methyl 3,4-Dihydroxybenzoate Induces Neural Stem Cells to Differentiate Into Cholinergic Neurons in vitro.

Neural stem cells (NSCs) have been shown as a potential source for replacing degenerated neurons in neurodegenerative diseases. However, the therapeutic potential of these cells is limited by the lack of effective methodologies for controlling their differentiation. Inducing endogenous pools of NSCs by small molecule can be considered as a potential approach of generating the desired cell types in large numbers. Here, we reported the characterization of a small molecule (Methyl 3,4-dihydroxybenzoate; MDHB) that selectively induces hippocampal NSCs to differentiate into cholinergic motor neurons which expressed synapsin 1 (SYN1) and postsynaptic density protein 95 (PSD-95). Studies on the mechanisms revealed that MDHB induced the hippocampal NSCs differentiation into cholinergic motor neurons by inhibiting AKT phosphorylation and activating autophosphorylation of GSK3ß at tyrosine 216. Furthermore, we found that MDHB enhanced ß-catenin degradation and abolished its entering into the nucleus. Collectively, this report provides the strong evidence that MDHB promotes NSCs differentiation into cholinergic motor neurons by enhancing gene Isl1 expression and inhibiting cell cycle progression. It may provide a basis for pharmacological effects of MDHB directed on NSCs.

Gene Expression Analysis Reveals Novel Gene Signatures Between Young and Old Adults in Human Prefrontal Cortex.

Human neurons function over an entire lifetime, yet the molecular mechanisms which perform their functions and protecting against neurodegenerative disease during aging are still elusive. Here, we conducted a systematic study on the human brain aging by using the weighted gene correlation network analysis (WGCNA) method to identify meaningful modules or representative biomarkers for human brain aging. Significantly, 19 distinct gene modules were detected based on the dataset GSE53890; among them, six modules related to the feature of brain aging were highly preserved in diverse independent datasets. Interestingly, network feature analysis confirmed that the blue modules demonstrated a remarkably correlation with human brain aging progress. Besides, the top hub genes including PPP3CB, CAMSAP1, ACTR3B, and GNG3 were identified and characterized by high connectivity, module membership, or gene significance in the blue module. Furthermore, these genes were validated in mice of different ages. Mechanically, the potential regulators of blue module were investigated. These findings highlight an important role of the blue module and its affiliated genes in the control of normal brain aging, which may lead to potential therapeutic interventions for brain aging by targeting the hub genes.

Heat-Induced Epithelial Barrier Dysfunction Occurs via C-Src Kinase and P120ctn Expression Regulation in the Lungs.

BACKGROUND/AIMS: Thermal injury causes pulmonary edema and can lead to death. Intercellular junctions are composed of adhesive (p120ctn, E-cadherin, α-catenin and ß-catenin) and compact (occludin and ZO-1) junctions. Heat deteriorates intercellular junctions and increases cell gaps to ultimately induce pulmonary edema, but the underlying mechanism remains elusive. METHODS: Mouse lung epithelial (MLE-12) cells pre-treated with the c-Src inhibitor PP2, p120ctn catenin (p120ctn) small interfering RNA and p120ctn catenin (p120ctn) complementary DNA were subjected to heat treatment. Western blotting and real-time polymerase chain reaction assays were used to evaluate junction protein expression changes after heat treatment, and co-immunoprecipitation was used to test the binding state of junction proteins. In addition, hematoxylin and eosin staining and immunohistochemistry were used to evaluate changes in junction protein expression and lung injury in a Wistar rat model of thermal inhalation injury. RESULTS: Heat increased cell permeability; induced ZO-1, occludin, α-catenin and ß-catenin degradation; and decreased E-cadherin distribution in cell membranes. Heat also activated c-Src and decreased both p120ctn expression levels and occludin and ZO-1 association. c-Src inhibitor (PP2) treatment and p120ctn overexpression reversed these effects and attenuated lung injury in vivo. CONCLUSION: Heat induces junction protein degradation and dissociation to increase membrane permeability and cause lung edema via c-Src kinase activation and p120ctn expression downregulation.

Methyl 3,4-Dihydroxybenzoate Enhances Resistance to Oxidative Stressors and Lifespan in C. elegans Partially via daf-2/daf-16.

Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span⁻extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.

A novel effective chemical hemin for the treatment of acute carbon monoxide poisoning in mice.

There is no effective drug for the therapy of acute carbon monoxide (CO) poisoning. The purpose of the present study was to investigate the potential preventive and therapeutic effects of hemin on an animal model of acute CO poisoning and to provide a potential therapeutic candidate drug. A total of 80 Kunming mice were randomly divided into four groups, namely the air control, acute CO poisoning, hemin-treatment + CO and hemin-pretreatment + CO groups (n=20 each). Furthermore, the mortality rate of mice, blood carboxyhaemoglobin (HbCO) concentration and serum malondialdehyde (MDA) concentration were measured, and pathological changes of the hippocampal area were determined using histochemical staining. The mice with acute CO poisoning had a 50% mortality rate at 1 h, with an increase in blood HbCO, serum MDA levels and pathological impairments of the hippocampus. Furthermore, the mortality rate, blood HbCO and serum MDA levels of mice with pretreatment and treatment of hemin were decreased. Additionally, the pathological changes of the hippocampal area were improved in the hemin-treatment and hemin-pretreatment groups compared with the mice treated with CO. These results suggest that hemin is a novel effective chemical for the prevention and treatment of acute CO poisoning in mice. Therefore, the present study provides a novel method and experimental basis for the application of hemin in treating patients with acute CO poisoning.

Neuroprotective effects of methyl 3,4 dihydroxybenzoate in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is a photoreceptor-degenerative disease that is currently untreatable and eventually causes blindness. Methyl 3,4 dihydroxybenzoate (MDHB) is a small molecule that exerts neuroprotective effects in vitro. The present study tests whether MDHB protects the retina of rd10 mice, a model of retinitis pigmentosa. MDHB or an equal volume of vehicle was intraperitoneally injected in rd10 mice daily from postnatal day 12 (P12) to P26. Retinal morphology was evaluated by immunostaining, and retinal function by electroretinogram (ERG) and by visual behavior. TUNEL, Iba1, GFAP staining and western blotting were applied to explore the neuroprotective mechanism of MDHB in retina. MDHB treatment significantly promoted photoreceptor survival and preserved cone morphology compared to the untreated animals. The visual behavior and ERG responses were also greatly enhanced in MDHB-treated rd10 mice. Mechanistically, following MDHB treatment, the number of TUNEL-positive cells was decreased in rd10 retina, and the expression of brain-derived neurotrophic factor (BDNF) protein and phosphorylated tropomyosin-related kinase B (TrkB) receptor were increased. Furthermore, blocking TrkB using the antagonist ANA-12 prevented the protective effect of MDHB on photoreceptor survival and structure. MDHB treatment also inhibited microglial activation and Muller cell gliosis in rd10 retina. In conclusion, MDHB treatment delays retinal degeneration in rd10 mice and preserves retinal structure and functions. These effects are likely mediated by the BDNF-TrkB pathway. Due to its neurotrophic effects and ability to reduce reactive gliosis, MDHB may be useful to treat degenerative diseases in retina and brain.

Role of amyloid ß protein receptors in mediating synaptic plasticity.

There are few diseases in modern biomedicine that have garnered as much scientific interest and public concern as Alzheimer's disease (AD). The amyloid hypothesis has become the dominant model of AD pathogenesis; however, the details of the hypothesis are changing over time. Recently, given the increasing recognition, subtle effects of amyloid ß protein (Aß) on synaptic efficacy may be critical to AD progression. Synaptic plasticity is the important neurochemical foundation of learning and memory. Recent studies have identified that soluble Aß oligomers combine with certain receptors to impair synaptic plasticity in AD, which advanced the amyloid hypothesis. The aim of the present review was to summarize the role of Aß-relevant receptors in regulating synaptic plasticity and their downstream signaling cascades, which may provide novel insights into the understanding of the pathogenesis of AD and the development of therapeutic strategies to slow down the progression of AD-associated memory decline in the early stages.

Running-induced memory enhancement correlates with the preservation of thin spines in the hippocampal area CA1 of old C57BL/6 mice.

The effects of prolonged physical training on memory performance and underlying synaptic mechanisms were investigated in old C57BL/6 mice. Training via voluntary running wheels was initiated at 16 months of age and continued for 5 months (1 hour per day and 5 days per week), followed by learning and memory test and spine/synapse analysis. Trained old mice were compared with their age-matched sedentary controls and aged adult controls. This training improved hippocampal-dependent spatial learning and memory function in old mice, and enhanced cognition was accompanied by increased density of spines on CA1 pyramidal cells in the hippocampus. Particularly, the training selectively affected thin spines that carry small synapses in the stratum radiatum, the target area of CA3 Schaffer pathway. Furthermore, increased density of thin spines positively correlates with improved memory performance. Finally, the training prevented age-related loss of postsynaptic density protein-95 in the Schaffer pathway. These data suggest that the preservation of thin spines carrying small synapses in specific hippocampal region contributes critically to running-related improvement of learning and memory function.

Neuroprotective Effects of Methyl 3,4-Dihydroxybenzoate against TBHP-Induced Oxidative Damage in SH-SY5Y Cells.

This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butyl hydroperoxide (TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM + 10% FBS for 24 h and pretreated with different concentrations of MDHB or N-acetyl-l-cysteine (NAC) for 4 h prior to the addition of 40 µM TBHP for 24 h. Cell viability was analyzed using the methylthiazolyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rates. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells.

RPS23RG1 reduces Aß oligomer-induced synaptic and cognitive deficits.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that ß-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's ß-amyloid (Aß) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aß oligomer (oAß)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAß-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAß-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAß-induced synaptic and cognitive deficits in AD.