Circular RNAs: emerging players in brain aging and neurodegenerative diseases.

Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.

Identification of Potential Therapeutic Targets of Alzheimer's Disease By Weighted Gene Co-Expression Network Analysis.

Objective Alzheimer's disease (AD) is the most common cause of dementia. The pathophysiology of the disease mostly remains unearthed, thereby challenging drug development for AD. This study aims to screen high throughput gene expression data using weighted co-expression network analysis (WGCNA) to explore the potential therapeutic targets.Methods The dataset of GSE36980 was obtained from the Gene Expression Omnibus (GEO) database. Normalization, quality control, filtration, and soft-threshold calculation were carried out before clustering the co-expressed genes into different modules. Furthermore, the correlation coefficients between the modules and clinical traits were computed to identify the key modules. Gene ontology and pathway enrichment analyses were performed on the key module genes. The STRING database was used to construct the protein-protein interaction (PPI) networks, which were further analyzed by Cytoscape app (MCODE). Finally, validation of hub genes was conducted by external GEO datasets of GSE 1297 and GSE 28146.Results Co-expressed genes were clustered into 27 modules, among which 6 modules were identified as the key module relating to AD occurrence. These key modules are primarily involved in chemical synaptic transmission (GO:0007268), the tricarboxylic acid (TCA) cycle and respiratory electron transport (R-HSA-1428517). WDR47, OXCT1, C3orf14, ATP6V1A, SLC25A14, NAPB were found as the hub genes and their expression were validated by external datasets.Conclusions Through modules co-expression network analyses and PPI network analyses, we identified the hub genes of AD, including WDR47, OXCT1, C3orf14, ATP6V1A, SLC25A14 and NAPB. Among them, three hub genes (ATP6V1A, SLC25A14, OXCT1) might contribute to AD pathogenesis through pathway of TCA cycle.

Decreased phototoxicity of photodynamic therapy by Cx32/Cx26-composed GJIC: A "Good Samaritan" effect.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) has been widely used to treat malignant tumors. Our previous studies indicated that connexin (Cx) 32- and Cx26-composed gap junctional intercellular communication (GJIC) could improve the phototoxicity of PDT. However, the role of heterotypic Cx32/Cx26-formed GJIC in PDT phototoxicity is still unknown. Thus, the present study was aimed to investigate the effect of Cx32/Cx26-formed GJIC on PDT efficacy. METHODS: CCK8 assay was used to detect cell survival after PDT. Western blot assay was utilized to detect Cx32/Cx26 expression. "Parachute" dye-coupling assay was performed to measure the function of GJ channels. The intracellular Ca2+ concentrations were determined using flow cytometer. ELISA assay was performed to detect the intracellular levels of PGE2 and cAMP. RESULTS: The present study demonstrates there is a Cx32/Cx26-formed GJIC-dependent reduction of phototoxicity when cells were exposure to low concentration of Photofrin. Such a protective action is missing at low cell density due to the lack of GJ coupling. Under high-cell density condition, where there is opportunity for the cells to contact each other and form GJ, suppressing Cx32/Cx26-formed GJIC by either inhibiting the expression of Cx32/Cx26 or pretreating with GJ channel inhibitor augments PDT phototoxicity after cells were treated with at 2.5 µg/ml Photofrin. The above results suggest that at low Photofrin concentration, the presence of Cx32/Cx26-formed GJIC may decrease the phototoxicity of PDT, leading to the insensitivity of malignant cells to PDT treatment. The GJIC-mediated PDT insensitivity was associated with Ca2+ and prostaglandin E2 (PGE2 ) signaling pathways. CONCLUSION: The present study provides a cautionary note that for tumors expressing Cx32/Cx26, the presence of Cx32/Cx26-composed GJIC may cause the resistance of tumor cells to PDT. Oppositely, treatment strategies designed to downregulate the expression of Cx32/Cx26 or restrain the function of Cx32/Cx26-mediated GJIC may increase the sensitivity of malignant cell to PDT. Lasers Surg. Med. 51:301-308, 2019. © 2019 Wiley Periodicals, Inc.

The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma.

BACKGROUND: Dysfunctions of long non-coding RNA (lncRNAs) have been associated with the initiation and progression of hepatocellular carcinoma (HCC), but the clinicopathologic significance and potential role of lncRNA PTTG3P (pituitary tumor-transforming 3, pseudogene) in HCC remains largely unknown. METHODS: We compared the expression profiles of lncRNAs in 3 HCC tumor tissues and adjacent non-tumor tissues by microarrays. In situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to assess the level of PTTG3P and prognostic values of PTTG3P were assayed in two HCC cohorts (n = 46 and 90). Artificial modulation of PTTG3P (down- and over-expression) was performed to explore the role of PTTG3P in tumor growth and metastasis in vitro and in vivo. Involvement of PTTG1 (pituitary tumor-transforming 1), PI3K/AKT signaling and its downstream signals were validated by qRT-PCR and western blot. RESULTS: We found that PTTG3P was frequently up-regulated in HCC and its level was positively correlated to tumor size, TNM stage and poor survival of patients with HCC. Enforced expression of PTTG3P significantly promoted cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, PTTG3P knockdown had opposite effects. Mechanistically, over-expression of PTTG3P up-regulated PTTG1, activated PI3K/AKT signaling and its downstream signals including cell cycle progression, cell apoptosis and epithelial-mesenchymal transition (EMT)-associated genes. CONCLUSIONS: Our findings suggest that PTTG3P, a valuable marker of HCC prognosis, promotes tumor growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in HCC and might represent a potential target for gene-based therapy.

[Preliminary establishment of integration of Alzheimer's disease and blood stasis syndrome tree shrew model and evaluation of intervention of Panax notoginseng saponins].

To establish the integration of Alzheimer's disease(AD) and blood stasis syndrome tree shrew model. Panax notoginseng saponins (PNS) was used to intervene the model to testify the stability of the model. The level of blood stasis of each group in the tree shrew model was evaluated by analyzing five traditional Chinese medicine(TCM) characterizations, four blood coagulation indexes, plasma nitric oxide (NO) level, plasma superoxide dismutase (SOD) level in each group. Hematoxylin and eosin(HE) staining was used to observe the morphological changes of brain hippocampal neuron cell of each group. Immunohistochemical staining was used to assay the ChAT and SYP levels in brain hippocampus of each group.The blood stasis characterization of the integration of disease and syndrome group was more obvious than the AD group, and that of the drug administration group was lower than that of the integration of disease and syndrome group. Aß1-42, APP, P-Tau, ChAT and SYP level of AD group were lower than those in the blank group, which were further reduced in the model of integration of disease and syndrome. However, the administration of PNS relieved the reduction, indicating that the AD and blood stasis integration syndrome tree shrew model is stable.

RP5-833A20.1/miR-382-5p/NFIA-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis and inflammatory reaction.

OBJECTIVE: Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide. Long noncoding RNAs are emerging as new players in gene regulation, but how long noncoding RNAs operate in the development of atherosclerosis remains unclear. APPROACH AND RESULTS: Using microarray analysis, we found that long noncoding RNA RP5-833A20.1 expression was upregulated, whereas nuclear factor IA (NFIA) expression was downregulated in human acute monocytic leukemia macrophage-derived foam cells. Moreover, we showed that long noncoding RNA RP5-833A20.1 may decreases NFIA expression by inducing hsa-miR-382-5p expression in vitro. We found that the RP5-833A20.1/hsa-miR-382-5p/NFIA pathway is essential to the regulation of cholesterol homeostasis and inflammatory responses in human acute monocytic leukemia macrophages. Lentivirus-mediated NFIA overexpression increased high-density lipoprotein cholesterol circulation, reduced low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol circulation, decreased circulation of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α, and C-reactive protein, enhanced reverse cholesterol transport, and promoted regression of atherosclerosis in apolipoprotein E-deficient mice. CONCLUSIONS: Our findings indicated that the RP5-833A20.1/miR-382-5p/NFIA pathway was essential to the regulation of cholesterol homeostasis and inflammatory reactions and suggested that NFIA may represent a therapeutic target to ameliorate cardiovascular disease.

miRNA-548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x-interacting protein.

AIM: miR-548p is a recently identified and poorly characterized miRNA. However, its role of miR-548p in tumorigenesis and progression remains poorly understood. Here, we aimed to investigate the biofunction of miR-548p in hepatocellular carcinogenesis. METHODS: The expression levels of miR-548p were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The role of miR-548p in hepatocellular carcinoma (HCC) was determined by colony formation, flow cytometry assay and nude mice xenograft experiments. miR-548p target genes were analyzed by miRNA target predication programs and verified by qRT-PCR, western blotting assay and dual-luciferase reporter assay. RESULTS: miR-548p is repressed by hepatitis B virus X protein (HBx) in HCC tumor tissues and hepatoma cells, and inhibited cell growth by inhibiting cell proliferation and promoting cell apoptosis. miR-548p directly downregulated the expression of hepatitis B x-interacting protein (HBXIP) by binding to the 3'-untranslated region of HBXIP mRNA. Further study showed that hepatocyte nuclear factor-4a (HNF4A) promoted the expression of miR-548p and inhibited the transcription of HBXIP. HNF4A is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis, and is shown to be repressed by HBx. CONCLUSION: We proposed the model for HBx/HNF4A/miR-548p/HBXIP pathway that controls hepatoma cell growth and tumorigenesis of HCC. miR-548p was identified as a tumor-suppressor in HBx-associated hepatocellular carcinogenesis.

The miR-573/apoM/Bcl2A1-dependent signal transduction pathway is essential for hepatocyte apoptosis and hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with an increasing incidence worldwide. Apolipoprotein M (apoM) is a novel apolipoprotein that is mainly expressed in liver and kidney tissues. However, the anti-tumor properties of apoM remain largely unknown. We evaluated the anti-tumor activities and mechanisms of apoM in HCC both in vivo and in vitro. Bioinformatic analysis and luciferase reporter assay results showed that apoM was a potential target of hsa-miR-573 and was downregulated after transfection with hsa-miR-573 mimics. Overexpression of apoM suppressed migration, invasion, and proliferation of hepatoma cells in vitro. Overexpression of hsa-miR-573 in hepatoma cells reduced apoM expression, leading to promotion of the invasion, migration, and proliferation of hepatoma cells in vitro. In addition, hsa-miR-573 markedly promoted growth of xenograft tumors in nude mice with an accompanying reduction in cell apoptosis. ApoM markedly inhibited growth of xenograft tumors in nude mice and promoted cell apoptosis. Moreover, Bcl2A1 mRNA and protein levels were inhibited by apoM overexpression and an increase in apoptosis rate by apoM was markedly compensated by Bcl2A1 overexpression in HepG2 cells. These results provide evidence that hsa-miR-573 promoted tumor growth by inhibition of hepatocyte apoptosis and this pro-tumor effect might be mediated through Bcl2A1 in an apoM-dependent manner. Therefore, our findings may be useful to improve understanding of the critical effects of hsa-miR-573 and apoM in HCC pathogenesis.

Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high prevalence and lethality. However, the underlying mechanism for HCC has not been entirely elucidated. Recent studies have highlighted the roles of long non-coding RNAs (lncRNAs) in carcinogenesis, and it is suggested that they might play critical roles in HCC progression. Here, we will briefly introduce the biology of lncRNAs, emphasizing the mechanisms and emerging roles of HCC-related lncRNAs. To date, HCC-related lncRNAs are demonstrated to influence the life cycle of genes by various means including epigenetic silencing, splicing regulation, lncRNA-miRNA interaction, lncRNA-protein interaction and genetic variation. Moreover, they can participate in diverse biological processes involved in HCC progression through impacts upon cell proliferation, apoptosis, invasion and metastasis and angiogenesis. Since lncRNA can present in body fluid and have good specificity and accessibility, some HCC-related lncRNAs are suggested to be useful as novel potential biomarkers for HCC diagnosis, prognosis and prediction of response to therapy. Those HCC-related lncRNAs may provide potential novel therapeutic targets for HCC and other diseases.

Ameliorative Role of Mitochondrial Therapy in Cognitive Function of Vascular Dementia Mice.

BACKGROUND: Mitochondrial dysfunction plays a vital role in the progression of vascular dementia (VaD). We hypothesized that transfer of exogenous mitochondria might be a beneficial strategy for VaD treatment. OBJECTIVE: The study was aimed to investigate the role of mitochondrial therapy in cognitive function of VaD. METHODS: The activity and integrity of isolated mitochondria were detected using MitoTracker and Janus Green B staining assays. After VaD mice were intravenously injected with exogenous mitochondria, Morris water maze and passive avoidance tests were used to detect cognitive function of VaD mice. Haematoxylin and eosin, Nissl, TUNEL, and Golgi staining assays were utilized to measure neuronal and synaptic injury in the hippocampus of VaD mice. Detection kits were performed to detect mitochondrial membrane potential (ΔΨ), SOD activity and the levels of ATP, ROS, and MDA in the brains of VaD mice. RESULTS: The results showed that isolated mitochondria were intact and active. Mitochondrial therapy could ameliorate cognitive performance of VaD mice. Additionally, mitochondrial administration could attenuate hippocampal neuronal and synaptic injury, improve mitochondrial ΔΨ, ATP level and SOD activity, and reduce ROS and MDA levels in the brains of VaD mice. CONCLUSIONS: The study reports profitable effect of mitochondrial therapy against cognitive impairment of VaD, making mitochondrial treatment become a promising therapeutic strategy for VaD.

Anti-inflammatory effects of propofol are mediated by apolipoprotein M in a hepatocyte nuclear factor-1α-dependent manner.

Propofol (2,6-diisopropylphenol) is probably the most widely used intravenous hypnotic agent in daily practice. However, its anti-inflammatory properties have seldom been addressed. In this study, we evaluated the anti-inflammatory activity and mechanisms of propofol on lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro and found that propofol markedly inhibited LPS-induced production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, and expression of inducible nitric oxide synthase (iNOS). At the same time, the expression of hepatocyte nuclear factor-1α (HNF-1α) and apolipoprotein M (APOM) was inhibited by treatment with LPS and LPS-induced down-regulation of HNF-1α expression and APOM expression could be compensated by propofol treatment. However, propofol could not compensate LPS-induced down-regulation of APOM expression by treatment with HNF-1α siRNA and the suppressive effect on LPS-induced pro-inflammatory cytokines production by propofol was significantly compensated by treatment with APOM siRNA. These results provide evidence that propofol may first up-regulate APOM expression by enhancing HNF-1α expression and then inhibit pro-inflammatory cytokine production in LPS-stimulated cells. Therefore, our study may be useful in understanding the critical effect of propofol in patients with systemic inflammatory response syndrome.

[Effect of PNS on the activity and content of BACE1 in the brain of SAMP8 mice with Alzheimer's disease].

OBJECTIVE: To explore the effect of Panax notoginseng saponin (PNS) on the activity and content of beta-secretase in the brain of senescence accelerated mouse-prone 8 (SAMP8) mice with Alzheimer's disease. METHODS: Totally 32 SAMP8 mice were randomly divided into the normal control group, the high dose PNS group (200 mg/kg), the low dose group (100 mg/kg), and the huperzine A group (0.3 mg/kg), 8 in each group. Equal volume of double distilled water was given to those in the normal control group. All medication was given by gastrogavage, once daily for two successive months. The activity of BACE1 was assayed by direct immunofluorescent method (DIF). The content of BACE1 protein was detected by Western blot. RESULTS: The relative fluorescence units (RFU/microg) was 2.008 +/- 0.031 in the high dose PNS group, 2.221 +/- 0.029 in the low dose PNS group, and 2.267 +/- 0.076 in the huperzine A group, all lower than that in the normal control group (2.403 +/- 0.058; all P < 0.01). The content of BACE1 protein was 0.900 +/- 0.028 in the high dose PNS group, 1.000 +/- 0.032 in the low dose PNS group, and 0.837 +/- 0.080 in the huperzine A group, all lower than that in the normal control group (2.210 +/- 0.074, all P < 0.01). CONCLUSION: PNS higher than 100 mg/kg could decrease the activity of BACE1 and down-regulate the content of BACE1 protein in the brain of SAMP8 mice.

[Study on the effect of extracts from the leaves of Phyllanthus emblica on immune function of mice].

OBJECTIVE: To explore the effect of extracts from the leaves of Phyllanthus emblica (PLFs) on the immune function of mice. METHODS: 70 Kunming mice were choosed to conduct the acute toxicity test of PLFs. The mice were randomly divided into four groups: PLFs high-dosage group, mid-dosage group, low-dosage group and control group. The high,mid,low-dosage groups were treated with PLFs 1.982, 0.991 and 0.496 g/kg respectively per day. The same volume of double distilled water was given to the control group. All by intragastric administration for 7 d. The animals were killed and indexes of thymus and spleen were calculated. The expurgation index K and phagocyte index a were detected after the mice being injected with a dilute India ink through caudal vein. In addition, prepared spleen cells conventionally,the activity of Natural Killer cells was measured and the proliferation of T and B cells were detected. The effect of the extracts on serum hemolysin was detected after the SRBC was injected into the enterocoelia. RESULTS: The LD50 of PLFs was 9. 911 g/kg. Compared with the control group, the indexes of thymus and spleen in the treatment groups had no markedly difference (P > 0.05). The high- and mid-dosage groups could obviously improve the expurgation index K (P < 0.05), phagocyte index alpha (P < 0.05) and NK cell activity (P < 0.05). CONCLUSION: The extracts from Phyllanthus emblica leaves can promote nonspecific immunity immune function in mice.

Gliclazide Ameliorates Neuronal Injury by Attenuating Oxidative Stress in D-gal-Induced Senescent Cells and Aging Mice.

Enhancement of oxidative stress and resultant neuronal injury play important roles in initiating cognitive impairment during the aging process. Thus, attenuating oxidative injury is regarded as a profitable therapeutic strategy for age-associated cognitive impairment. Previous studies showed that gliclazide (Gli) had a protective role in neuronal injury from cerebral ischemia/reperfusion (I/R) injury. However, whether Gli has a profitable effect on age-associated cognitive impairment remains largely unclear. The present study showed that Gli held the potential to attenuate neuronal apoptosis in D-gal-induced senescent cells and aging mice. Additionally, Gli could alleviate synaptic injury and cognitive function in D-gal-induced aging mice. Further study showed that Gli could attenuate oxidative stress in D-gal-induced senescent cells and aging mice. The p38 MAPK pathway was predicted as the downstream target of Gli retarding oxidative stress using in silico analysis. Further studies revealed that Gli attenuated D-gal-induced phosphorylation of p38 and facilitated Nrf2 nuclear expression, indicating that the anti-oxidative property of Gli may be associated with the p38 MAPK pathway. The study demonstrates that Gli has a beneficial effect on ameliorating D-gal-induced neuronal injury and cognitive impairment, making this compound a promising agent for the prevention and treatment of age-associated cognitive impairment.

[The effect of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with alzheimer's disease].

OBJECTIVE: To explore the effects of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with Alzheimer's disease. METHODS: SAMP8 mice were randomly divided into four groups: PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. The high-dosage group and low-dosage group were treated with 200 and 100 mg/kg PNS respectively per day and the huperzine A group was treated with 0.3 mg/kg huperzine A per day, all by intragastric administration for 8 consecutive weeks. The same volume of double distilled water was given to the control group. The activity of a-secretase was assayed by direct immunofluorescent method(DIF). Western blot was used to detect the content of alpha-secretase including ADAM9, ADAM10 and ADAM17 proteins. RESULTS: The Relative Fluorescence Units (RFU) of PNS high-dosage and low-dosage groups were higher than that of control group (P < 0.01). The results of western blot showed that the level of ADAM9 protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly higher than that of control group (P < 0.05) while the levels of ADAM10 protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly lower than that of control group (P < 0.05), while level of ADAM17 of huperzine A group was higher than that of control group (P < 0.05). CONCLUSION: PNS can increase activity of alpha-secretase in the brain of SAMP8 mouse via increasing the level of ADAM9 protein expression.

Corrigendum: A Novel Role of Connexin 40-Formed Channels in the Enhanced Efficacy of Photodynamic Therapy.

[This corrects the article DOI: 10.3389/fonc.2019.00595.].

Erratum: Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway: Erratum.

[This corrects the article DOI: 10.7150/ijbs.55453.].

[Study of galic acid extracted from the leaves of Phyllanthus emblica on apoptotic mechanism of human hepatocellular carcinoma cells BEL-7404].

OBJECTIVE: To explore the mechanism of apoptosis of human hepatocellular carcinoma cells BEL-7404 induced by Galic acid extracted from leaves of Phyllanthus emblica. METHODS: PI/Hoechst33342 double staining method was utilized to observe the influence on cell life cycle. The expressions of Bax and Bcl-2 protein were determined by fluorescence immunostaining and Western blot. RESULTS: The results from PI/Hoechst33342 double staining method indicated that the percentage of cells G2/M phases increased after treated for 72 h, the phenomenon of blockage appeared and cell death was induced. Fluorescence immunostaining showed that the expression of Bax was up-regulated, and the expression of Bcl-2 was down-regulated. Western blot also showed that the the expression of Bax was up-regulated. CONCLUSION: The mechanism of human hepatoma BEL-7404 cells apoptosis induced by Galic acid from leaves of Phyllanthus emblica may be blocking G2/M period in cell life cycle, up-regulating the expression of Bax and down-regulating the expression of Bcl-2, that can decrease membrane potential of mitochondria,and triggered the caspases of activation of cascade and induced cell death.

[Effect of Panax notoginseng saponins on APP gene transcription in the brain tissue of SAMP8].

OBJECTIVE: To study the effect of Panax notoginseng saponins (PNS) on learning and memory ability and APP gene transcription in the brain tissue in senescence accelerated mouse prone 8 (SAMP8). METHODS: SAMP8 were randomly divided into high-does PNS group, low-does PNS group, huperzin A group and model group,the treatment groups were treated with the designed drugs respectively by intragastric administration for 4 consecutive weeks. The same volume of double distilled water was given to model group. After treatment, the abilities of learning and memory of the mice were tested with morris water maze, the mRNA content of APP was assayed by reverse transcription (RT) and real-time polymerase chain reaction (RT-PCR). RESULTS: PNS could improve the abilities of learning and memory, high-does PNS could reduce the mRNA content of APP in the brain tissue of SAMP8. CONCLUSION: PNS can improve the abilities of learning and memory of SAMP8, the mechanism may be relevant to down-regulating the expression of APP gene at transcriptional level.

Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway.

Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.