High level of ANO1 promotes pancreatic cancer growth in concert with oncogenic KRAS.

BACKGROUND: Anoctamin-1 (ANO1) was identified as an unfavorable prognostic marker in pancreatic cancer. However, the exact implication of ANO1 in pancreatic cancer is still poorly understood. Here we investigated the effect of ANO1 in pancreatic cancer progression under the context of oncogenic KRAS, aiming at finding a new therapeutic target. METHODS: Knockdown and overexpression of oncogenic KRAS as well as ANO1 in PDAC cell lines were performed by lentivirus infection. Cell proliferation and migration assay, RNA seq analysis were performed in PDAC cells bearing different status of ANO1 and KRAS. In vivo mice model was used to investigate the xenograft tumor growth with different status of KRAS and ANO1. RESULTS: Our results showed that ANO1 expression level is elevated in poorly differentiated cancer cells. Overexpression of ANO1 in PDAC cancer cells was found to promote cancer cell proliferation in vitro and in vivo, which synergized with the introduction of oncogenic KRAS. Consistently, knockdown of ANO1 expression was found to suppress cancer growth in vitro and in vivo. RNA seq analysis revealed that the observed synergistic cancer-promoting effect from ANO1 and oncogenic KRAS is likely due to concurrent activating key genes involved in lipid metabolism including HMGCS1. CONCLUSION: The outcome from our study suggests that ANO1 plays an important role in promoting pancreatic cancer development, especially at the presence of oncogenic KRAS. Considering the prevalence of KRAS mutation in pancreatic cancer patients, suppression ANO1 may represent a potential effective therapeutic measure in pancreatic cancer treatment.

Inhibited HDAC3 promotes microRNA-376c-3p to suppress malignant phenotypes of gastric cancer cells by reducing WNT2b.

OBJECTIVE: Our study aims to identify the impact of histone deacetylase 3 (HDAC3) and microRNA-376c-3p (miR-376c-3p) on gastric cancer (GC) by targeting wingless-type MMTV integration site family member 2b (WNT2b). METHODS: Levels of miR-376c-3p, HDAC3 and WNT2b were assessed. GC cells were treated with altered HDAC3 or miR-376c-3p to evaluate their biological functions, and rescue experiment was performed to assess the effect of WNT2b on GC cells. The tumor growth in vivo was observed. RESULTS: HDAC3 and WNT2b were up-regulated while miR-376c-3p was reduced in GC tissues and cell lines. The inhibited HDAC3 or elevated miR-376c-3p could restrain malignant behaviors of GC cells in vitro, and also suppress the xenograft growth. WNT2b silencing reduced the effect of miR-376c-3p inhibition while WNT2b overexpression mitigated that of miR-376c-3p promotion on GC cell growth. CONCLUSION: Inhibiting HDAC3 promotes miR-376c-3p to suppress malignant phenotypes of GC cells via reducing WNT2b, thereby restricting GC development.

Thymosin ß4 reverses phenotypic polarization of glial cells and cognitive impairment via negative regulation of NF-κB signaling axis in APP/PS1 mice.

BACKGROUND: Thymosin ß4 (Tß4) is the most abundant member of the ß-thymosins and plays an important role in the control of actin polymerization in eukaryotic cells. While its effects in multiple organs and diseases are being widely investigated, the safety profile has been established in animals and humans, currently, little is known about its influence on Alzheimer's disease (AD) and the possible mechanisms. Thus, we aimed to evaluate the effects and mechanisms of Tß4 on glial polarization and cognitive performance in APP/PS1 transgenic mice. METHODS: Behavior tests were conducted to assess the learning and memory, anxiety and depression in APP/PS1 mice. Thioflavin S staining, Nissl staining, immunohistochemistry/immunofluorescence, ELISA, qRT-PCR, and immunoblotting were performed to explore Aß accumulation, phenotypic polarization of glial cells, neuronal loss and function, and TLR4/NF-κB axis in APP/PS1 mice. RESULTS: We demonstrated that Tß4 protein level elevated in all APP/PS1 mice. Over-expression of Tß4 alone alleviated AD-like phenotypes of APP/PS1 mice, showed less brain Aß accumulation and more Insulin-degrading enzyme (IDE), reversed phenotypic polarization of microglia and astrocyte to a healthy state, improved neuronal function and cognitive behavior performance, and accidentally displayed antidepressant-like effect. Besides, Tß4 could downregulate both TLR4/MyD88/NF-κB p65 and p52-dependent inflammatory pathways in the APP/PS1 mice. While combination drug of TLR4 antagonist TAK242 or NF-κB p65 inhibitor PDTC exerted no further effects. CONCLUSIONS: These results suggest that Tß4 may exert its function by regulating both classical and non-canonical NF-κB signaling and is restoring its function as a potential therapeutic target against AD.

Single housing-induced effects on cognitive impairment and depression-like behavior in male and female mice involve neuroplasticity-related signaling.

Single-housed stress elicits a range of social isolation-related behavioral and neurobiological abnormalities. To investigate single housing-induced behavioral changes and sex differences on stress outcomes, we examined single-housed stress-induced learning and memory impairment, depression-like behaviors, neuroplasticity abnormalities and underlying mechanism. The results showed that male and female mice socially isolated for 8 weeks had significantly decreased memory acquisition, as demonstrated in the learning curve of the Morris water maze task. Memory consolidation and retrieval were also decreased in both the single-housed male and female mice. These findings were corroborated further by the two classical animal models, Y-maze and novel object recognition tests, as demonstrated by reduced spontaneous alternation and recognition index in both sexes of single-housed mice. Subsequent studies suggested that single-housed male mice exhibited increased immobility time in both the forced swim and tail suspension tests, while the female mice only exhibited increased immobility time in the tail suspension test. Moreover, single-housed stress significantly decreased the apical and basal branch points, dendritic length, and spine density in the CA1 of hippocampal neurons in both male and female mice. These effects were consistent with decreased neuroplasticity and neuroprotective-related molecules such as synaptophysin, PSD95, PKA, pCREB and BDNF expression. These findings suggest that loss of neuronal remodeling and neuroprotective mechanisms due to single housing are involved in behavioral changes in both male and female mice. The results provide further evidence that neuroplasticity-related signaling plays a crucial role in isolation-induced effects on neuropsychiatric behavioral deficits in both sexes.

Modulation of the MAPKs pathways affects Aß-induced cognitive deficits in Alzheimer's disease via activation of α7nAChR.

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aß1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aß-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aß internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aß-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aß-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aß-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

Ginsenoside-Rd Promotes Neurite Outgrowth of PC12 Cells through MAPK/ERK- and PI3K/AKT-Dependent Pathways.

Panax ginseng is a famous herbal medicine widely used in Asia. Ginsenosides have been identified as the principle active ingredients for Panax ginseng's biological activity, among which ginsenoside Rd (Rd) attracts extensive attention for its obvious neuroprotective activities. Here we investigated the effect of Rd on neurite outgrowth, a crucial process associated with neuronal repair. PC12 cells, which respond to nerve growth factor (NGF) and serve as a model for neuronal cells, were treated with different concentrations of Rd, and then their neurite outgrowth was evaluated. Our results showed that 10 µM Rd significantly increased the percentages of long neurite- and branching neurite-bearing cells, compared with respective controls. The length of the longest neurites and the total length of neurites in Rd-treated PC12 cells were much longer than that of respective controls. We also showed that Rd activated ERK1/2 and AKT but not PKC signalings, and inhibition of ERK1/2 by PD98059 or/and AKT by LY294002 effectively attenuated Rd-induced neurite outgrowth. Moreover, Rd upregulated the expression of GAP-43, a neuron-specific protein involved in neurite outgrowth, while PD98059 or/and LY294002 decreased Rd-induced increased GAP-43 expression. Taken together, our results provided the first evidence that Rd may promote the neurite outgrowth of PC12 cells by upregulating GAP-43 expression via ERK- and ARK-dependent signaling pathways.

Neurotrophic keratopathy due to dorsolateral medullary infarction (Wallenberg syndrome): case report and literature review.

BACKGROUND: Dorsolateral medullary infarction (Wallenberg syndrome) is rare in clinical practice; however, the subsequent corneal lesions are more uncommon. To our knowledge, only one such case was previously reported. We report a similar case with successful treatment and recovery, and analyse both cases to address the clinical features and outcomes of such syndrome. CASE PRESENTATION: A 43-year-old male presented with neurotrophic keratopathy one month after sustaining dorsolateral medullary infarction. The patient underwent amniotic membrane transplantation twice. Two-year follow-up observation revealed changes in nerve fibers and epithelial cells of corneal by laser confocal microscopy. CONCLUSION: By studying both cases, we confirm that neurotrophic keratopathy could be as a delayed-onset complication of Wallenberg syndrome. The recognition that neurotrophic keratopathy can follow dorsolateral medullary infarction could prevent the clinical misdiagnosis.

Design and Synthesis of Low Surface Energy Coating with Functionalized Al2O3 Nanoparticles.

In a high-moisture environment where dust and coastal saltwater are prevalent, the stability of power equipment can be adversely affected. This issue can result in equipment downtime, particularly for transformers, severely disrupting the continuous operation of DC transmission systems. To address this challenge, a superhydrophobic modified fluorosilicone coating was developed, incorporating anti-stain properties. To tackle this issue comprehensively, an orthogonal experiment was conducted, involving six factors and three levels. The study focused particularly on assessing the impact of water-repellent recovery agents, nanofillers, antistatic agents, anti-mold agents, leveling agents, as well as wetting and dispersing agents on the coating's surface tension. The results demonstrate that selecting an appropriate base resin and incorporating well-matched functional additives played a central role in effectively reducing the surface tension of the coating. Consequently, optimized coatings exhibited exceptional resistance to stains and displayed strong corrosion resistance.

Fabrication of a Fluorocarbon Low Surface Energy Coating for Anti-Stain Applications.

In the long-term working state, stains such as dust, oil, and charged particles in the environment are prone to deposit on the surface of the power equipment, which has great security risks. To achieve anti-stain performance, fluorocarbon composite coating with a low surface energy was prepared and studied. In this paper, SiO2 nanoparticles were used as inorganic fillers and fluorocarbon resin was used as the substrate to form anti-stain coatings. By adjusting and optimizing the ratio of fillers and organic resins, coatings with different static contact angles were constructed. The optimum composite coating has a contact angle of 151 ± 2° and a surface energy of 9.6 mJ/m2. After high-temperature treatment (up to 200 °C), immersion in corrosive solutions (pH 3-11), and sandpaper abrasion (after 5 abrasion cycles), the coating has been proven to show good thermal, chemical and mechanical stability. Our study provides significant research and market opportunities for the anti-stain application of the fluorocarbon composite coating on power equipment.

Podocyte injury and overexpression of vascular endothelial growth factor and transforming growth factor-beta 1 in adriamycin-induced nephropathy in rats.

The aim of this study is to investigate the expression of nephrin, vascular endothelial growth factor (VEGF), transforming growth factor-beta 1 (TGF-ß1), and podocyte number in adriamycin (ADR)-induced nephropathy. A total of 60 male Sprague-Dawley rats were randomly divided into the control group and the ADR nephropathy group. The nephropathy was induced by tail-vein injection of ADR (4 mg/kg) twice at a 14-day interval. The expression levels of nephrin, VEGF, and TGF-ß1 in glomeruli were assessed by immunohistochemistry and western blotting. The podocyte number was also evaluated after anti-Wilms' tumor-1 (WT1) immunohistochemical staining. In addition, the urinary protein content, biochemical parameters in serum samples and glomerular sclerosis index (SI) were compared between groups. In the ADR nephropathy group, the expression levels of nephrin was significantly decreased with the fusion of podocyte foot processes at 6 weeks after the first ADR injection, which was associated with a marked proteinuria. A decrease in podocyte number and an increase in SI with the overexpression of both VEGF and TGF-ß1 were also observed in the glomeruli at 10 weeks after the first ADR injection. This was associated with focal segmental glomerulosclerosis (FSGS). The study data suggest that podocyte injury and decreased nephrin, as well as increased VEGF and TGF-ß1, may contribute to the development of proteinuria and FSGS in ADR-induced nephropathy in rats.

[Prokaryotic expression and immunogenicity of the chimeric HBcAg containing Aß(1-15)].

OBJECTIVE: To construct a recombinant prokaryoticexpression plasmid pET/ c-Aß(15)-c, and evaluate the immunogenicity of its encoded fusion protein as expressed in E.coli. METHODS: The gene fragment HBc88-144 was amplified by PCR and subcloned to pUC19. The synthetic, double-strand Aß(1-15) gene was inserted downstream of HBc1-71 in pGEMEX/c1-71. After restriction enzyme digestion, c1-71- Aß(15) was spliced to HBc88-144, yielding the recombinant gene c-Aß(15)-c; that gene was subcloned into pET-28a(+). The fusion protein (CA15C) expressed in the transformed E.coli BL21 was induced with isopropyl ß-D-1-thiogalactopyranoside (IPTG) and analyzed by SDS-PAGE. The virus-like particle (VLP) formed by fusion protein CA15C was observed with transmission electric microscope (TEM). Four Kunming (KM) mice were given intraperitoneal injections of CA15C, and the anti-Aß antibody elicited was detected by indirect ELISA. RESULTS: The sequence of the recombinant gene was confirmed by restriction enzyme digestion and DNA sequencing. After IPTG induction, the fusion protein was expressed, mainly in the sediment from the bacterial lysate. The expression level was 40% of total protein in the sediment. The CA15C could form VLP. After 5 rounds of immunization, the titer of anti-Aß antibody in the sera of KM mice reached 1:10000, while the anti-HBc antibody was undetectable. CONCLUSION: Recombinant c-Aß(15)-c gene can be expressed in E.coli. The expressed protein can form VLPs and has a strong immunogenicity.

Research trend of microbiota-gut-brain axis in Alzheimer's disease based on CiteSpace (2012-2021): A bibliometrics analysis of 608 articles.

Background: Recently, research on the microbiota-gut-brain axis (MGBA) has received increasing attention, and the number of studies related to Alzheimer's disease (AD) has increased rapidly, but there is currently a lack of summary of MGBA in AD. Objective: To capture research hotspots, grasp the context of disciplinary research, and explore future research development directions. Methods: In the core dataset of Web of Science, documents are searched according to specific subject words. CiteSpace software is used to perform statistical analysis on measurement indicators such as the number of published papers, publishing countries, institutions, subject areas, authors, cocited journals, and keywords, and to visualize of a network of relevant content elements. Results: The research of MGBA in AD has shown an upward trend year by year, and the cooperation between countries is relatively close, and mainly involves the intersection of neuroscience, pharmacy, and microbiology. This research focuses on the relationship between MGBA and AD symptoms. Keyword hotspots are closely related to new technologies. Alzheimer's disease, anterior cingulate cortex, inflammatory degeneration, dysbiosis, and other research are the focus of this field. Conclusion: The study revealed that the research and development of MGBA in AD rapidly progressed, but no breakthrough has been made in the past decade, it still needs to be closely combined with multidisciplinary technology to grasp the frontier hotspots. Countries should further strengthen cooperation, improve the disciplinary system, and increase the proportion of empirical research in all research.

Tß4 ameliorates oxidative damage and apoptosis through ERK/MAPK and 5-HT1A signaling pathway in Aß insulted SH-SY5Y cells.

AIMS: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder seriously endangering the physical and mental health of the elderly, while no effective treatments and drugs in clinical practice are available. Thymosin ß4 (Tß4) is a multifunctional polypeptide involved in many physiological and pathological processes including AD. This study aims to understand the function and molecular mechanism of Tß4 in the development of AD. MAIN METHODS: Neuroblastoma cell line SH-SY5Y was treated with ß-amyloid (Aß) to induce AD-like pathological changes, which serves as Alzheimer's disease model. Tß4 was overexpressed in SH-SY5Y cells by lentivirus infection, and downregulated by siRNA transfection. Apoptosis of transfected SH-SY5Y cells after Aß-treatment was examined by western blot and flow cytometry. Apoptotic proteins and Tß4-related signaling pathways were also investigated by western blot. KEY FINDINGS: We found that Tß4 overexpression increased viability and suppressed apoptosis of Aß-treated SH-SY5Y cells. Tß4 ameliorated oxidative damage and suppressed reactive oxygen species production in Aß-treated SH-SY5Y cells. Consistently, Tß4 overexpression down-regulated the expression levels of pro-apoptotic markers such as Caspase-3, Caspase-8, and Bax, while up-regulated the expression level of anti-apoptotic gene Bcl-2 in Aß-stimulated SH-SY5Y cells. Mechanistically, we demonstrated that Tß4 dampened ERK/p38 MAPK signaling and enhanced 5-HTR1A expression in Aß-treated SH-SY5Y cells. Moreover, we revealed that Tß4 inhibited the activation of ERK pathway through up-regulating 5-HTR1A in Aß-treated SH-SY5Y cells. SIGNIFICANCE: Taken together, our findings provide evidences to support the neuroprotective role of Tß4 and might open up new therapeutic applications of Tß4 in AD treatment.

TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway.

Overactivated microglia and neuroinflammation are considered to play a crucial role in the progression of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells-2 (TREM2), a type I transmembrane receptor, expressed uniquely by microglia in the brain, is involved in the neuroinflammatory responses of AD. In this study, to further explore the precise effects of TREM2 on neuroinflammation and the underlying mechanisms in AD, we employed a lentiviral-mediated strategy to overexpress TREM2 in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and cultured BV2 cells. Our results showed that TREM2 overexpression rescued cognitive deficits, decreased ß-amyloid (Aß) plaques deposition, reduced synaptic and neuronal loss, as well as ameliorated neuroinflammation. The mechanistic study revealed that these protective effects were likely attributed to inhibition of neuroinflammatory responses through the JAK/STAT/SOCS signaling pathway and subsequent attenuation of pro-inflammatory cytokines. Furthermore, suppression of neuroinflammation might be ascribed to activation of the M2 microglia, as the levels of M2 phenotype markers Arg-1, IL-10 and Ym1 were markedly increased. Similarly, overexpression of TREM2 in BV2 cells also promoted M2 polarization and led to the alleviation of M1 microglial inflammatory responses through JAK/STAT/SOCS signaling pathway, suggesting that TREM2 is an important factor in shifting the microglia from M1 to M2 phenotype. Taken together, our results further provide insights into the role of TREM2 in AD pathogenesis and highlight TREM2 as a potential target against AD.

Dexamethasone inhibits camptothecin-induced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway.

Dexamethasone (DX) induces apoptosis resistance in most solid malignant tumors during co-treatment with chemotherapy agents, such as camptothecin (CAM). In this study, we investigated the mechanism by which DX reduces chemotherapy efficiency in C6-glioma. DX reduced CAM-increased DNA fragmentation and caspase-3 activation. The DX's protection was negated by RU486, an antagonist of glucocorticoid receptor (GR). DX itself increased anti-apoptotic gene, Bcl-xL expression, and its transcription factor, signaling transducer and activator of transcription 5 (Stat5), DNA binding activity and phospho-Stat5 expression. DX blocked the CAM-decreased Bcl-xL and phospho-Stat5 expression, and Stat5 binding activity. RU486 negated DX's actions. To determine whether Stat5 regulates Bcl-xL expression in CAM-induced cell death, C6-glioma was infected with an adenovirus containing a constitutively activated Stat5-GFP (Ad-Stat5ca). Overexpression of Stat5ca increased Bcl-xL and decreased CAM-induced cell death compared to control adenovirus infected cells; whereas Stat5 siRNA decreased DX-induced Bcl-xL and increased cell death. Phospho-Stat5 expression was observed in the nuclear extract by co-immunoprecipitation with an anti-GR antibody, indicating that Stat5 and GR were interactive and formed a complex in the nuclei. These results suggest that DX's prevention from CAM-induced apoptosis and RU486's antagonism of DX's protection may be through Stat5/Bcl-xL signal pathway regulated by a GR.

[Podocyte injury and expression of nephrin and VEGF in rat nephrosis model induced by adriamycin].

OBJECTIVE: To investigate podocyte injury and the expression of nephrin and VEGF in rat nephrosis model induced by adriamycin. METHODS: The rat adriamycin induced nephrosis model was established, while the biochemical indicators in blood and urine were measured and the pathological changes of the renal tissue were evaluated by light microscope and electron microscope. The podocyte number was counted, and the expression levels of nephrin, VEGF were examined at different time by means of immunohistochemistry. RESULTS: After second injected with adriamycin,the model group nephrin presented a weak signal in the end of the first week (P < 0.05), and the expression of VEGF started to increase at the end of the eighth week (P < 0.05). The podocyte number decreased at the end of the eighth week (P < 0.05). The expression of nephrin and the number of podocyte were negatively correlated with the 24-hour urine protein, blood urea nitrogen and serum creatinine; while the expression of VEGF was positively correlated with the 24-hour urine protein, blood urea nitrogen and serum creatinine. CONCLUSION: The decrease of nephrin expression and the change of its distribution might be the significant factors resulting in considerable proteinuria. VEGF participated in the process of proteinuria and glomerular sclerosis in the development of rat adriamycin nephrosis.

[Effect of tanshinone IIA on the change of calcium current induced by beta-amyloid protein 25-35 in neurons of nucleus basalis of Meynert].

OBJECTIVE: To explore the effect of tanshinone IIA (TanIIA) on calcium current induced by beta-amyloid protein 25-35 (Abeta25-35) in neurons of nucleus basalis of Meynert (nbM). METHODS: Cell acute dissociated technique and the whole-cell recording model of patch-clamp technique of single-cell were used. The voltage-dependent calcium current in neurons of nbM was recorded in SD rats first. Then the effect of TanIIA on the voltage-dependent calcium current in the neurons was assayed. The change of calcium current induced by Abeta25-35 as well as the effect of TanIIA on the change of calcium current induced by Abeta25-35 in neurons of nbM were analyzed. RESULTS: Extracellular fluid containing different concentrations of TanIIA was irrigated, respectively. The peak current did not change obviously. There was no difference in current density between the TanIIA group and the control group at 0 mV (P>0.05). Extracellular fluid containing 200 nmol/L Abeta25-35 was irrigated after the normal calcium current recorded under whole patch clamp, and the peak current changed obviously. There was distinct difference in the current density between the Abeta group and the control group at 0 mV (P<0.05). Extracellular fluid containing Abeta25-35 and different concentrations of TanIIA were irrigated after the normal calcium current was recorded under whole patch clamp, respectively, and the peak current did not change. There was no difference in current density between the TanIIA +Abeta group and the control group at 0 mV (P>0.05). CONCLUSION: In vitro, TanIIA could inhibit the calcium current amplification induced by Abeta25-35 in neurons of nbM. TanIIA may protect neurons against the toxicity of Abeta and decrease the inward flow of Ca(2+).

5-HT1AR alleviates Aß-induced cognitive decline and neuroinflammation through crosstalk with NF-κB pathway in mice.

The 5-hydroxytryptamine (5-HT) receptor is significant for the regulation of mood and memory. However, the role of 5-HT1AR in ß-Amyloid protein (Aß)-induced cognitive decline, neuroinflammation and the possible mechanism remains elusive. Thus, we aimed to evaluate the effects of 5-HT1AR on Aß-induced learning and memory decline and neuroinflammation in mice. Novel object recognition and Morris water maze tests were performed to observe learning and memory behavior in mice. Protein levels of Iba1, GFAP, MAP2, TNF-α, Tß4, C-fos, IKK-ß, IKB-α, NF-κBp65, phospho-NF-κBp65 in the hippocampus were examined by immunostaining or western blotting. Aß1-42-treatment inducing learning and memory decline was shown in novel object recognition and Morris water maze tests; neuroinflammation shown in immunostaining. Our study found out that 5-HT1AR inhibitor WAY100635 showed significant improvement in Aß-induced learning and memory decline. Moreover, WAY100635 decreases levels of Iba1, GFAP, and TNF-α in the hippocampus, which were related to neuroinflammation. While treatment with 5-HT1AR agonist 8-OH-DPAT or ERK inhibitor U0126 exerted no effects or even aggravated Aß-induced learning and memory decline. In addition, WAY100635 could downregulate phospho-NF-κB in the hippocampus of Aß1-42-injected mice. These results provide new insight into the mechanism, for 5-HT1AR in Aß-induced cognitive impairments through crosstalk with the NF-κB signaling pathway. Our data indicated that WAY100635 was involved in the protective effects against neuroinflammation and improvement of learning and memory in Alzheimer's disease.

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7.

Malignant gliomas are the most common tumor in central nervous system with poor prognosis. Due to the limitation of histological classification in earlier diagnosis and individualized medicine, it is necessary to combine the molecular signatures and the pathological characteristics of gliomas. Lots of microRNAs presented abnormal expression in gliomas and modulated gliomas development. Exploration the miRNAs profile is helpful for the diagnosis, therapy and prognosis of gliomas. It has been demonstrated that miR-144 plays important roles in solid tumors. However, the detail mechanisms remained unrevealed. In this study, we have demonstrated the level of miR-144 decreased in glioma tissues from patients, especially in gliomas with higher grades. MiR-144 was also validated have lower expression in glioma cell lines compared with cortical neuron cell by using qRT-PCR. The in vitro functional experiment indicated miR-144 improved gliomas progression through repressing proliferation, sensitizing to chemotherapeutics and inhibiting metastasis. We further identified fibroblast growth factor 7 (FGF7) and Caveolin 2 (CAV2) were target genes of miR-144 by luciferase reporter assay and western blotting. The mechanisms study suggested forced FGF7 expression elevated Akt activation and decreased reactive oxygen species (ROS) generation. The MTT and cell cycle assay indicated miR-144 suppressed glioma cells proliferation through modulating FGF mediated Akt signaling pathway. Meanwhile, miR-144 promoted Temozolomide (TMZ) induced apoptosis in glioma cells via increasing ROS production by using FACS. On the other hand, CAV2, as another target of miR-144, accelerated glioma cells migration and invasion via promoting glioma cells EMT progress. Retrieved expression of FGF7 or CAV2 rescued the proliferation and migration function mediated by miR-144. Furthermore, the in vivo experiments in PDX models displayed the anti-tumor function of miR-144, which could be retrieved by overexpression of FGF7 and CAV2. Taken together, these findings indicated miR-144 acted as a potential target against gliomas progression and uncovered a novel regulatory mechanism, which may provide a new therapeutic strategy and prognostic indicator for gliomas.

PNU282987 alleviates Aß-induced anxiety and depressive-like behaviors through upregulation of α7nAChR by ERK-serotonin receptors pathway.

Patients with Alzheimer's disease often undergo anxiety and depression. Our previous studies have shown that α7nAChR protects against Aß-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of α7nAChR on Aß-induced anxiety and depressive-like behaviors and the effect of α7nAChR on the regulation of MAPKs pathways remain unknown. To examine the effects of α7nAChR and MAPKs pathways on Aß-induced anxiety and depression-like behaviors and to explore their relationships between them, elevated plus maze, open field and forced swim tests were performed. Protein levels of 5-HT1A receptor, 5-HT2C receptor, α7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that Aß oligomers induced anxiety and depression-like behaviors in C56BL/6 mice with open field, elevated plus maze and forced swim tests. However, activation of α7nAChR or inhibition of ERK pathways showed significant antidepressant and anxiolytic-like effects on Aß-injected mice. Moreover, Aß significantly decreased the level of 5-HT1A receptor but increased the level of 5-HT2C receptor in the basolateral amygdala. Treatment with α7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed Aß-induced 5-HT1A and 5-HT2C receptor changes. Moreover, activation of α7nAChR inhibited ERK pathway in the amygdala of Aß1-42-injected mice. Our study provides a new insight into the mechanism of α7nAChR in Aß-induced depression and anxiety-related symptoms through the regulation of ERK1/2 pathway and the potential association with serotonin receptors. Together, our data suggests that α7nAChR is protective against Aß-induced anxiety and depression-like behaviors in mice.