ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

KDM4B down-regulation facilitated breast cancer cell stemness via PHGDH upregulation in H3K36me3-dependent manner.

Despite recent advances have been made in clinical treatments of breast cancer, the general prognosis of patients remains poor. Therefore, it is imperative to develop a more effective therapeutic strategy. Lysine demethylase 4B (KDM4B) has been reported to participate in breast cancer development recently, but its exact biological role in breast cancer remains unclear. Here, we observed that KDM4B was down-regulated in human primary BRCA tissues and the low levels of KDM4B expression were correlated with poor survival. Gain- and loss-of-function experiments showed that KDM4B inhibited the proliferation and metastasis of breast cancer cells. Besides, knockdown of KDM4B promoted the epithelial-mesenchymal transition (EMT) and cell stemness in breast cancer cells. Mechanistically, KDM4B down-regulates PHGDH by decreasing the enrichment of H3K36me3 on the promoter region of PHGDH. Knockdown of PHGDH could significantly reversed proliferation, migration, EMT, and cell stemness induced by KDM4B silencing in breast cancer cells. Collectively, we propose a model for a KDM4B/PHGDH axis that provides novel insight into breast cancer development, which may serve as a potential factor for predicting prognosis and a therapeutic target for breast cancer.

A Cys2/His2 Zinc Finger Protein Acts as a Repressor of the Green Revolution Gene SD1/OsGA20ox2 in Rice (Oryza sativa L.).

Gibberellins (GAs) play important roles in the regulation of plant growth and development. The green revolution gene SD1 encoding gibberellin 20-oxidase 2 (GA20ox2) has been widely used in modern rice breeding. However, the molecular mechanism of how SD1/OsGA20ox2 expression is regulated remains unclear. Here, we report a Cys2/His2 zinc finger protein ZFP207 acting as a transcriptional repressor of OsGA20ox2. ZFP207 was mainly accumulated in young tissues and more specifically in culm nodes. ZFP207-overexpression (ZFP207OE) plants displayed semidwarfism phenotype and small grains by modulating cell length. RNA interference of ZFP207 caused increased plant height and grain length. The application of exogenous GA3 could rescue the semidwarf phenotype of ZFP207OE rice seedlings. Moreover, ZFP207 repressed the expression of OsGA20ox2 via binding to its promoter region. Taken together, ZFP207 acts as a transcriptional repressor of SD1/OsGA20ox2 and it may play a critical role in plant growth and development in rice through the fine-tuning of GA biosynthesis .

GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway.

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates for cell survival. Glutaminase (GLS1) is over-expressed in multiple cancers, including colorectal cancer (CRC). However, the role of GLS1 in colorectal cancer development has not yet fully elucidated. In this study, we found that GLS1 levels were significantly increased in CRC cells. Knockdown of GLS1 by shRNAs as well as GLS1 inhibitor BPTES decreased DLD1 and SW480 cell proliferation, colony formation and migration. Knockdown of GLS1 as well as BPTES induced reactive oxygen species (ROS) production, down-regulation of GSH/GSSG ratio, an decrease in Nrf2 protein expression and an increase in cytoplasmic Nrf2 protein expression in DLD1 and SW480 cells. Furthermore, Knockdown of GLS1 as well as BPTES inhibited autophagy pathway, antioxidant NAC and Nrf2 activator could reversed inhibition of GLS1-mediated an decrease in autophagic flux in DLD1 and SW480 cells. Depletion of GLS1-induced inhibition of DLD1 and SW480 CRC cell proliferation, colony formation and migration was reversed by autophagy inducer rapamycin. These results suggest that targeting GLS1 might be a new potential therapeutic target for the treatment of CRC.

OsSYP121 Accumulates at Fungal Penetration Sites and Mediates Host Resistance to Rice Blast.

Magnaporthe oryzae is a fungal pathogen that causes rice (Oryza sativa) blast. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are key components in vesicle trafficking in eukaryotic cells and are known to contribute to fungal pathogen resistance. Syntaxin of Plants121 (SYP121), a Qa-SNARE, has been reported to function in nonhost resistance in Arabidopsis (Arabidopsis thaliana). However, the functions of SYP121 in host resistance to rice blast are largely unknown. Here, we report that the rice SYP121 protein, OsSYP121, accumulates at fungal penetration sites and mediates host resistance to rice blast. OsSYP121 is plasma membrane localized and its expression was obviously induced by the rice blast in both the blast-resistant rice landrace Heikezijing and the blast-susceptible landrace Suyunuo (Su). Overexpression of OsSYP121 in Su resulted in enhanced resistance to blast. Knockdown of OsSYP121 expression in Su resulted in a more susceptible phenotype. However, knockdown of OsSYP121 expression in the resistant landrace Heikezijing resulted in susceptibility to the blast fungus. The POsSYP121 ::GFP-OsSYP121 accumulated at rice blast penetration sites in transgenic rice, as observed by confocal microscopy. Yeast two-hybrid results showed that OsSYP121 can interact with OsSNAP32 (Synaptosome-associated protein of 32 kD) and Vesicle-associated membrane protein714/724. The interaction between OsSYP121 and OsSNAP32 may contribute to host resistance to rice blast. Our study reveals that OsSYP121 plays an important role in rice blast resistance as it is a key component in vesicle trafficking.

FOXM1 facilitates breast cancer cell stemness and migration in YAP1-dependent manner.

Breast cancer has the highest incidence and mortality in the female population. Forkhead box M1 (FOXM1) known as a transcription factor is upregulated and associated with poor prognosis in a variety of cancers. However, the molecular mechanisms of FOXM1 on breast cancer progression are poorly understood. In this study, we found that FOXM1 was up-regulated in breast cancer. FOXM1 promoted cell proliferation, clonal formation, and migration capacity in triple negative breast cancer by increasing transcriptional activity of YAP1. FOXM1 also maintained cell stemness via the Hippo pathway. The YAP1-TEAD binding inhibitor Verteporfin reduced the transcription level of OCT4 and NANOG but the Hippo pathway activator XMU-MP-1 could increase the transcription level of OCT4 and NANOG. In summary, our findings indicated that FOXM1 promoted breast cancer progression through the Hippo pathway, and it was suggested a new strategy to treat breast cancer.

KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming.

Lysine demethylase 5B (KDM5B) is up-regulated in many cancers, including breast cancer. However, the underlying metabolic mechanisms of KDM5B on breast cancer progression are poorly understood. Here, we showed that KDM5B expression positively correlates with metastasis in breast cancer. Cell functional analyses were demonstrated that KDM5B knockdown and KDM5B inhibitor AS-8351 inhibited breast cancer cell proliferation and migration. Furthermore, we reported that KDM5B knockdown and AS-8351 reversed epithelial-mesenchymal transition (EMT) and decreased the protein levels of fatty acid synthase (FASN) and ATP citrate lyase (ACLY) in MCF-7 and MDA-MB-231 cells. Interestingly, we found that activation of AMP-activated protein kinase (AMPK) signaling pathway is involved in KDM5B-mediated EMT and lipid metabolism reprogramming in breast cancer cells. As a result, silencing of KDM5B-induced activation of AMPK signaling pathway inhibited breast cancer cell proliferation and migration. Taken together, our findings indicated that KDM5B was a novel regulator of lipid metabolism reprogramming, and it was suggested a new strategy to treat breast cancer.

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus.

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.

Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis.

Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF-E2-related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch-like ECH-associated protein 1 (Keap1) reduced the expression of glucose-6-phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia-inducing factor 1α (HIF-1α) in MCF-7 and MDA-MB-231 cells. Overexpression of Nrf2 up-regulated the expression of Notch1 via G6PD/HIF-1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES-1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2-driven breast cancer metastasis.

Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1.

Colorectal cancer (CRC) is the third-leading cause of cancer mortality worldwide. HACE1 function as a tumor-suppressor gene and is downregulated in several kinds of cancers. However, the distribution and clinical significance of HACE1 in CRC is still not clarified. In this study, we found that the HACE1 expression is greatly downregulated in CRC tissues and cell lines. Moreover, the HACE1 expression was significantly associated with inhibition of CRC cell proliferation, metastasis, and invasion. HACE1 inhibited epithelial-mesenchymal transition in CRC cells. Furthermore, we found that HACE1 altered the protein expression of the Hippo pathway by downregulation of YAP1. HACE1 suppresses the invasive ability of CRC cells by negatively regulating the YAP1 pathway. Our data indicates that HACE1 directly targets YAP1 and induces downregulation of YAP1, thereby increasing the activity of the Hippo pathway. In summary, these findings demonstrated that HACE1-YAP1 axis had an important part in the CRC development and progression.

Loss of TET1 facilitates DLD1 colon cancer cell migration via H3K27me3-mediated down-regulation of E-cadherin.

Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration, and invasion in DLD1 cells. Loss of TET1 increased EZH2 expression and reduced UTX-1 expression, thus increasing histone H3K27 tri-methylation causing repression of the target gene E-cadherin. Ectopic expression of the H3K27 demethylase UTX-1 or EZH2 depletion both impeded EZH2 binding caused a loss of H3K27 methylation at epithelial gene E-cadherin promoter, thereby suppressing EMT and tumor invasion in shTET1 cells. Conversely, UTX-1 depletion and ectopic expression of EZH2 enhanced EMT and tumor metastasis in DLD1 cells. These findings provide insight into the regulation of TET1 and E-cadherin and identify EZH2 as a critical mediator of E-cadherin repression and tumor progression.

PKM2-mediated inhibition of autophagy facilitates Tat's inducing HIV-1 transactivation.

Considerable evidence has shown that autophagy has an important role in HIV-1 infection. However, it is still unknown whether metabolism-regulated autophagy pathway is involved in Tat-mediated HIV-1 transactivation. This study demonstrated that treatment of Tat in TZM-bl cells significantly down-regulated protein levels of Beclin-1, Atg-5, Atg-7, and LC3B-II and up-regulated of p62 levels. Blockage of autophagy enhanced Tat-induced HIV-1 transactivation in TZM-bl cells. Moreover, we found that Tat activated the Akt/mTOR and inhibited AMPK signaling pathway that was related to its up-regulation of PKM2 expression. In addition, we showed that PI3K/AKT activation and AMPK inhibtion was required for the PKM2-mediated inhibition of autophagy in Tat-treated TZM-bl cells. In conclusion, our data reveals that PKM2-mediated autophagy inhibition is required for Tat-mediated HIV-1 transactivation. Metabolism-related autophagic pathway may act as a promising diagnostic and therapeutic tool for HIV-1 infection in the future.

Tanshinone â ¡A inhibits human esophageal cancer cell growth through miR-122-mediated PKM2 down-regulation.

Pyruvate kinase M2 (PKM2) plays a pivotal role in the growth, survival and metabolic reprogramming of cancer cells. Here, we presented for the first time that tanshinone ⅡA inhibited human esophagus cancer cell growth through miR-122-mediated PKM2 down-regulation pathway. Tanshinone ⅡA inhibited cell proliferation and induced cell cycle arrest in S phase in human Ec109 cells. As expected, tanshinone ⅡA down-regulated PKM2 mRNA and protein expression in Ec109 cells. Given these findings, we further investigated microRNAs regulation of PKM2 and confirmed miR-122 for targeting PKM2. Moreover, we found that tanshinone ⅡA-induced up-regulation of miR-122 expression inhibited PKM2 expression in Ec109 cells. Meanwhile, tanshinone ⅡA inhibited proliferation through miR122-medated PKM2 down-regulation. It was demonstrated that the anticancer activity of tanshinone ⅡA was targeted at metabolic regulation of miR-122/PKM2 in human esophagus cancer cells. Taken together, our results revealed tanshinone ⅡA targeting at PKM2-mediated metabolic reprogramming play an important role in inhibition of esophageal cancer cell growth.

PAX1 Methylation Hallmarks Promising Accuracy for Cervical Cancer Screening in Asians: Results from a Meta-Analysis.

BACKGROUND: DNA methylation has been proposed as a potential biomarker for cervical cancer detection. This study aimed to evaluate the diagnostic role of paired boxed gene 1 (PAX1) methylation for cervical cancer screening in Asians. METHODS: Eligible studies were retrieved by searching the electronic databases, and the quality of the enrolled studies was assessed via the quality assessment for studies of diagnostic accuracy (QUADAS) tool. The bivariate meta-analysis model was employed to generate the summary receiver operator characteristic (SROC) curve using Stata 12.0 software. Cochran's Q test and I2 statistics were applied to assess heterogeneity among studies. Publication bias was evaluated by the Deeks' funnel plot asymmetry test. RESULTS: A total of 9 articles containing 15 individual studies were included. The SROC analysis showed that single PAX1 methylation allowed for the discrimination between cancer/high-grade squamous intraepithelial lesion (HSIL) patients and normal individuals with a sensitivity (95% confidence interval) of 0.80 (0.70 - 0.87) and specificity of 0.89 (0.86 - 0.92), corresponding to an area under curve (AUC) of 0.92. Notably, our subgroup analysis suggested that combing parallel testing of PAX1 methylation and HPV DNA (AUC, sensitivity, and specificity of 0.90, 0.82, and 0.84, respectively) seemed to harbor higher accuracy than single HPV DNA testing (AUC, sensitivity, and specificity of 0.81, 0.86, and 0.67, respectively). CONCLUSIONS: PAX1 methylation hallmarks a potential diagnostic value for cervical cancer screening in Asians, and parallel testing of PAX1 methylation and HPV in cervical scrapings confers an improved accuracy than single HPV DNA testing.

Effects of Xingbi gel on leukotriene E4 and immunoglobulin E production and nasal eosinophilia in a guinea pig model for allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal airways.Many therapies do not have immediate effects,even which have side-effects.However,the effects of Xingbi gel for the treatment of AR was investigated. OBJECTIVE: We investigated the effects of Xingbi gel on serum levels of leukotriene E4 (LTE4) and immunoglobulin E (IgE), as well as eosinophil counts in the nasal mucosa using a guinea pig model of allergic rhinitis (AR). METHODS: In addition to a healthy control group without AR, guinea pigs with AR were randomly divided into untreated AR control group, low-dose Xingbi gel (0.2483 g/mL) group, high-dose Xingbi gel (0.4966 g/mL) group, and budesonide group. RESULTS: Compared to the healthy controls, untreated AR guinea pigs had significantly higher ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts (p <0.01). Treatments with low-dose Xingbi gel, high-dose Xingbi gel, and budesonide significantly reduced the ethology scores, serum LTE4 and IgE levels, and nasal mucosa eosinophil counts as compared to untreated AR model guinea pigs (p <0.01). CONCLUSION: Xingbi gel alleviates AR in part through inhibiting LTE4 and IgE production and reducing eosinophilia in the nasal mucosa.

Tanshinone II A inhibits tat-induced HIV-1 transactivation through redox-regulated AMPK/Nampt pathway.

Tat transactivating activity regulated by NAD(+) -dependent histone deacetylase sirtuin1 (SIRT1) connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD(+) biosynthesis. Nampt, SIRT1, and AMPK were involved in inhibiting HIV-1 transactivation through redox-regulated pathway. Tanshinone II A is a main lipid-soluble monomer derivative from the root of Salvia miltiorrhiza (Danshen) and tanshinone II A possess a variety of biological activities through redox signaling pathway. Here we investigated the effect of tanshinone II A on Tat-induced HIV-1 transactivation and the redox signaling pathway involved in it. As the results were shown, tanshinone II A reversed Tat-induced reactive oxygen species (ROS) production and down-regulation of glutathione (GSH) levels in TZM-bl cells through up-regulation of Nrf2 expression. Tanshinone II A reversed Tat-induced inhibition of SIRT1 activity but not SIRT1 protein expression. Tanshinone II A reversed Tat-induced inhibition of Nampt protein expression and depletion of NAD(+) levels in TZM-bl cells in a dose-dependent manner. Tanshinone II A-evoked Nampt expression was mediated by AMPK signaling pathway. Tanshinone II A inhibited Tat-induced HIV-1 LTR transactivation dependent on AMPK-Nampt pathway. Collectively, our data provide new insights into understanding of the molecular mechanisms of tanshinone II A inhibited Tat-regulated transcription, suggesting that targeting AMPK/Nampt/SIRT1 pathway could serve as new anti-HIV-1 agents.

OsSLI1, a homeodomain containing transcription activator, involves abscisic acid related stress response in rice (Oryza sativa L.).

Homeodomain-leucine zipper type I (HD-Zip I) proteins are involved in the regulation of plant development and response to environmental stresses. In this study, OsSLI1 (Oryza sativa stress largely induced 1), encoding a member of the HD-Zip I subfamily, was isolated from rice. The expression of OsSLI1 was dramatically induced by multiple abiotic stresses and exogenous abscisic acid (ABA). In silico sequence analysis discovered several cis-acting elements including multiple ABREs (ABA-responsive element binding factors) in the upstream promoter region of OsSLI1. The OsSLI1-GFP fusion protein was localized in the nucleus of rice protoplast cells and the transcriptional activity of OsSLI1 was confirmed by the yeast hybrid system. Further, it was found that OsSLI1 expression was enhanced in an ABI5-Like1 (ABL1) deficiency rice mutant abl1 under stress conditions, suggesting that ABL1 probably negatively regulates OsSLI1 gene expression. Moreover, it was found that OsSLI1 was regulated in panicle development. Taken together, OsSLI1 may be a transcriptional activator regulating stress-responsive gene expression and panicle development in rice.

Amino acid metabolism, redox balance and epigenetic regulation in cancer.

Amino acids act as versatile nutrients driving cell growth and survival, especially in cancer cells. Amino acid metabolism comprises numerous metabolic networks and is closely linked with intracellular redox balance and epigenetic regulation. Reprogrammed amino acid metabolism has been recognized as a ubiquitous feature in tumour cells. This review outlines the metabolism of several primary amino acids in cancer cells and highlights the pivotal role of amino acid metabolism in sustaining redox homeostasis and regulating epigenetic modification in response to oxidative and genetic stress in cancer cells.

Ferroptosis resistance in cancer: recent advances and future perspectives.

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death and has been implicated in the occurrence and development of various diseases, including heart disease, nervous system diseases and cancer. Ferroptosis induction recently emerged as an attractive strategy for cancer therapy. Ferroptosis has become a potential target for intervention in these diseases or injuries in relevant preclinical models. This review summarizes recent progress on the mechanisms of ferroptosis resistance in cancer, highlights redox status and metabolism's role in it. Combination therapy for ferroptosis has great potential in cancer treatment, especially malignant tumors that are resistant to conventional therapies. This review will lead us to have a comprehensive understanding of the future exploration of ferroptosis and cancer therapy. A deeper understanding of the relationship between ferroptosis resistance and metabolism reprogramming may provide new strategies for tumor treatment and drug development based on ferroptosis.

Comprehensive review of amino acid transporters as therapeutic targets.

The solute carrier (SLC) family, with more than 400 membrane-bound proteins, facilitates the transport of a wide array of substrates such as nutrients, ions, metabolites, and drugs across biological membranes. Amino acid transporters (AATs) are membrane transport proteins that mediate transfer of amino acids into and out of cells or cellular organelles. AATs participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, redox regulation, and neurological regulation. Several AATs have been found to significantly impact the progression of human malignancies, and dysregulation of AATs results in metabolic reprogramming affecting tumor growth and progression. However, current clinical therapies that directly target AATs have not been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, the molecular mechanisms in human diseases such as tumors, kidney diseases, and emerging therapeutic strategies for targeting AATs.