Soluble humic acid suppresses plant immunity and ethylene to promote soybean nodulation.

Symbiotic nitrogen fixation (SNF) is a crucial process for nitrogen geochemical cycling and plant-microbe interactions. Water-soluble humic acid (WSHM), an active component of soil humus, has been shown to promote SNF in the legume-rhizobial symbiosis, but its molecular mechanism remains largely unknown. To reveal the SNF-promoting mechanism, we conducted transcriptomic analysis on soybean treated with WSHM. Our findings revealed that up- and downregulated differentially expressed genes (DEGs) were mainly involved in plant cell-wall/membrane formation and plant defence/immunity in the early stage, while the late stage was marked by the flavonoid synthesis and ethylene biosynthetic process. Further study on representative DEGs showed that WSHM could inhibit GmBAK1d-mediated immunity and BR signalling, thereby promoting rhizobial colonisation, infection, and nodulation, while not favoring pathogenic bacteria colonisation on the host plant. Additionally, we also found that the ethylene pathway is necessary for promoting the soybean nodulation by WSHM. This study not only provides a significant advance in our understanding of the molecular mechanism of WSHM in promoting SNF, but also provides evidence of the beneficial interactions among the biostimulator, host plant, and soil microbes, which have not been previously reported.

Researches of calcium-activated chloride channel ANO1 intervening amyotrophic lateral sclerosis progression by activating EGFR and CaMKII signaling.

BACKGROUND: ANO1 is closely correlated with the activation of EGFR and CaMKII, while EGFR and CaMKII show low activation in amyotrophic lateral sclerosis (ALS) models. Therefore, we designed experiments to verify that ANO1 may play a protective role on motor neurons in ALS by activating EGFR and CaMKII. METHODS: The expression changes of ANO1, EGFR, CaMKII, pEGFR, and pCaMKII, cell survival status, and apoptosis were studied by western blot, real-time quantitative PCR, immunofluorescence, immunohistochemistry, CCK-8, and flow cytometry. The role of ANO1 in the ALS model by activating EGFR and CaMKII was studied by applying corresponding activators, inhibitors, gene silencing, and overexpression. RESULTS: In hSOD1G93A transgenic animals and cell lines, low expression of ANO1 and low activation of EGFR and CaMKII were identified. ANO1 expression decreased gradually with the progression of ALS. Overexpression of ANO1 in the hSOD1G93A cell line and primary neurons of hSOD1G93A transgenic mice increased cell viability and decreased cell apoptosis. After the application of ANO1 inhibitor CaCC-inhA01 in hSOD1G93A cell line and primary neurons of hSOD1G93A transgenic mice, EGFR activator EGF and CaMKII activator Carbachol, increased cell viability and reduced cell apoptosis. After ANO1 was overexpressed in the hSOD1G93A cell line and primary neurons of hSOD1G93A transgenic mice, EGFR inhibitor AEE788 and CaMKII inhibitor KN93 decreased cell viability and increased cell apoptosis. CONCLUSIONS: Our results suggest that ANO1 plays an important role in the survival of ALS motor neurons. ANO1 can increase cell activity and reduce apoptosis by activating EGFR and CaMKII signals.

LINP1 represses unfolded protein response by directly inhibiting eIF2α phosphorylation to promote cutaneous squamous cell carcinoma.

BACKGROUND: Endoplasmic reticulum stress (ER stress) may destroy endoplasmic reticulum homeostasis (ER homeostasis) and leads to programmable cell death. Unfolded protein response (UPR) originally stimulated by ER stress is critical for the survival of tumor cells through trying to re-establish ER homeostasis as an adaption to harsh microenvironment. However, mechanisms involving key regulators in modulating UPR remain underexplored. METHODS: The expression of LINP1 in cutaneous squamous cell carcinoma (cSCC) tissues and cell lines was assessed. Subsequently, LINP1 was knocked out, knocked down or overexpressed in cSCC cells. CCK-8 assays, colony forming assays, transwell migration assays and invasiveness measurement by matrigel-coated transwell were performed to examine the role of LINP1 in cSCC development through gain-of-function and loss-of-function experiments. Transcriptomic sequencing (RNA-Seq) was conducted and indicated the key downstream signaling events regulated by LINP1 including UPR and apoptosis signaling. Furthermore, the direct interaction between LINP1 and eIF2α to modulate UPR and apoptosis was confirmed by RNA pulldown, RNA immunoprecipitation (RIP), ChIP-qPCR and in vitro phosphorylation assays. RESULTS: In this study, LncRNA in non-homologous end joining pathway 1 (LINP1) was identified to be one of the top ten highest-expressed LncRNAs in cSCC, the second most common cancer in the world. Functional studies using in vitro and in vivo models revealed that LINP1 functions as an oncogene to promote cell proliferation, colony formation, migration and invasiveness while inhibiting cell apoptosis in cSCC. Transcriptomic sequencing after knockdown of LINP1 indicated LINP1 negatively regulates UPR-related pathways involving key effectors for activating UPR and the apoptosis following the prolonged UPR. Mechanistic study showed LINP1 physically interacts with eIF2α to inhibit its phosphorylation for avoiding unmitigated UPR. Loss of LINP1 followed by enhanced eIF2α phosphorylation led to overactivated UPR and induced DDIT3 expression, contributing to ER stress-induced apoptosis and suppression of cSCC development. CONCLUSIONS: Our findings demonstrate a novel regulatory hierarchy of UPR by demonstrating LINP1 as a critical modulator for eIF2α phosphorylation and a suppressor of UPR-mediated apoptosis, which suggests a novel therapeutic target for cSCC treatment.

Resveratrol rescues cutaneous radiation-induced DNA damage via a novel AMPK/SIRT7/HMGB1 regulatory axis.

Cutaneous radiation injury (CRI) interrupts the scheduled process of radiotherapy and even compromises the life quality of patients. However, the current clinical options for alleviating CRI are relatively limited. Resveratrol (RSV) has been shown to be a promising protective agent against CRI; yet the mechanisms of RSV enhancing radioresistance were not fully elucidated and limited its clinical application. In this study, we demonstrate RSV promotes cutaneous radioresistance mainly through SIRT7. During ionizing radiation (IR) treatment, RSV indirectly phosphorylates and activates SIRT7 through AMPK, which is critical for maintaining the genome stability of keratinocytes. Immunoprecipitation and mass spectrometry identified HMGB1 to be the key interacting partner of SIRT7 to mediate the radioprotective function of RSV. Mechanistic study elucidated that SIRT7 interacts with and deacetylates HMGB1 to redistribute it into nucleus and "switch on" its function for DNA damage repair. Our findings establish a novel AMPK/SIRT7/HMGB1 regulatory axis that mediates the radioprotective function of RSV to alleviate IR-induced cutaneous DNA injury, providing an efficiently-curative option for patients with CRI during radiotherapy.

Magic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation.

Microtubules (MTs) and their associated proteins play essential roles in maintaining cell structure, organelle transport, cell motility, and cell division. Two motors, kinesin and cytoplasmic dynein link the MT network to transported cargos using ATP for force generation. Here, we report an all-atom NMR structure of nucleotide-free kinesin-1 motor domain (apo-KIF5B) in complex with paclitaxel-stabilized microtubules using magic-angle-spinning (MAS) NMR spectroscopy. The structure reveals the position and orientation of the functionally important neck linker and how ADP induces structural and dynamic changes that ensue in the neck linker. These results demonstrate that the neck linker is in the undocked conformation and oriented in the direction opposite to the KIF5B movement. Chemical shift perturbations and intensity changes indicate that a significant portion of ADP-KIF5B is in the neck linker docked state. This study also highlights the unique capability of MAS NMR to provide atomic-level information on dynamic regions of biological assemblies.

Development and validation of four ferroptosis-related gene signatures and their correlations with immune implication in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This tumor presents with an insidious onset, rapid progression, and frequent recurrence. Ferroptosis is a newly discovered mode of programmed cell death that may play a key role in the progression of HCC. This study aimed to investigate the prognostic value of ferroptosis-related genes (FRGs) in HCC and their impact on tumor immune function, thereby providing new insights into targeted therapy for HCC. First, 43 differentially expressed FRGs were identified using the TCGA database, and four prognostically relevant methylation-driven FRGs (G6PD, HELLS, RRM2, and STMN1) were screened via survival and methylation analyses. Gene co-expression, mutation, and clinicopathological characterization indicated that these four pivotal FRGs play essential roles in tumor progression. We also validated these four genes using transcriptomic and proteomic data as well as cohort samples from our patients. Moreover, receiver operator characteristic (ROC) curves confirmed that the signatures of the four FRGs were independent prognostic factors in HCC. Gene set enrichment analysis of the four FRGs showed statistically significant associations with pathways related to HCC proliferation. Finally, the TIMER and TISIDB databases indicated that the four FRGs were statistically significantly correlated with tumor-infiltrating immune cells and immune checkpoint expression. Taken together, this study provides information guiding a novel therapeutic strategy targeting FRGs for HCC treatment.

Integrated Bioinformatic Analysis Identifies TIPIN as a Prognostic Biomarker in Hepatocellular Carcinoma.

BACKGROUND: Gene expression and DNA methylation analyses have long been used to identify cancer markers. However, a combination analysis of the gene expression and DNA methylation has yet to be performed to identify potential biomarkers of hepatocellular carcinoma (HCC). METHODS: By matching gene expression profiles and promoter methylation data in The Cancer Genome Atlas (TCGA), genes with discrepant expression as well as genes with differential promoter methylation were identified. High-expression genes with low promoter methylation were defined as epigenetically induced (EI), while low-expression genes with high promoter methylation were defined as epigenetically suppressed (ES). The human protein interaction network was further integrated to construct the EI/ES gene interaction network, and the key genes in the subnet were identified as potential HCC biomarkers. The expression differences and prognostic values were verified in TCGA and Gene Expression Omnibus (GEO) databases, as well as with tissue chip technology. RESULTS: Four key genes were identified: TIPIN, RBM15B, DUSP28, and TRIM31, which demonstrated the differential gene expression and prognostic value in TCGA and GEO databases. Tissue microarray analysis (TMA) revealed that TIPIN levels were altered in HCC. The upregulated TIPIN expression was associated with worse overall survival. Univariate and multivariate analyses showed that the TIPIN expression was an independent predictor of HCC. CONCLUSION: TIPIN might be a potential novel prognostic biomarker for HCC.

An overview on the biological activity and anti-cancer mechanism of lovastatin.

Lovastatin, a secondary metabolite isolated from fungi, is often used as a representative drug to reduce blood lipid concentration and treat hypercholesterolemia. Its structure is similar to that of HMG-CoA. Lovastatin inhibits the binding of the substrate to HMG-CoA reductase, and strongly competes with HMG-CoA reductase (HMGR), thereby exerting a hypolipidemic effect. Further, its safety has been confirmed in vivo and in vitro. Lovastatin also has anti-inflammatory, anti-cancer, and neuroprotective effects. Therefore, the biological activity of lovastatin, especially its anti-cancer effect, has garnered research attention. Several in vitro studies have confirmed that lovastatin has a significant inhibitory effect on cancer cell viability in a variety of cancers (such as breast, liver, cervical, lung, and colon cancer). At the same time, lovastatin can also increase the sensitivity of some types of cancer cells to chemotherapeutic drugs and strengthen their therapeutic effect. Lovastatin inhibits cell proliferation and regulates cancer cell signaling pathways, thereby inducing apoptosis and cell cycle arrest. This article reviews the structure, biosynthetic pathways, and applications of lovastatin, focusing on the anti-cancer effects and mechanisms of action.

PAK4 suppresses motor neuron degeneration in hSOD1G93A -linked amyotrophic lateral sclerosis cell and rat models.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons (MN). CREB pathway-mediated inhibition of apoptosis contributes to neuron protection, and PAK4 activates CREB signalling in diverse cell types. This study aimed to investigate PAK4's effect and mechanism of action in ALS. METHODS: We analysed RNA levels by qRT-PCR, protein levels by immunofluorescence and Western blotting, and apoptosis by flow cytometry and TUNEL staining. Cell transfection was performed for in vitro experiment. Mice were injected intraspinally to evaluate PAK4 function in vivo experiment. Rotarod test was performed to measure motor function. RESULTS: The expression and activation of PAK4 significantly decreased in the cell and mouse models of ALS as the disease progressed, which was caused by the negative regulation of miR-9-5p. Silencing of PAK4 increased the apoptosis of MN by inhibiting CREB-mediated neuroprotection, whereas overexpression of PAK4 protected MN from hSOD1G93A -induced degeneration by activating CREB signalling. The neuroprotective effect of PAK4 was markedly inhibited by CREB inhibitor. In ALS models, the PAK4/CREB pathway was inhibited, and cell apoptosis increased. In vivo experiments revealed that PAK4 overexpression in the spinal neurons of hSOD1G93A mice suppressed MN degeneration, prolonged survival and promoted the CREB pathway. CONCLUSIONS: PAK4 protects MN from degeneration by activating the anti-apoptotic effects of CREB signalling, suggesting it may be a therapeutic target in ALS.

Molecular Characteristics of N1-Methyladenosine Regulators and Their Correlation with Overall Cancer Survival.

N1-methyladenosine (m1A) is a prevalent RNA modification widely affecting RNA structural stability, folding, and interactions with proteins. Recently, there have been increasing reports on the roles of m1A regulators in tumors. However, their mechanisms and clinical relevance remain unclear. This study systematically evaluates the epigenetic characteristics and clinical relevance of m1A regulators using bioinformatic methods. Our results show widespread gene expression changes for m1A regulators, which are related to the activation and inhibition of carcinogenic pathways and overall patient survival. Collectively, this investigation provides new insights into assessing tumor prognosis and targeted therapy.

Correlations between stemness indices for hepatocellular carcinoma, clinical characteristics, and prognosis.

Recent studies have shown that cancer stem cells (CSCs) are involved in the occurrence and development of hepatocellular carcinoma (HCC). However, potential mechanisms for this have not yet been elucidated. We constructed a model based on the Progenitor Cell Biology Consortium database to generate stemness indices. We then utilized RNA-seq data and clinical information from the Cancer Genome Atlas (CGA) and International Cancer Genome Consortium (ICGC) for model predictions and verification. An mRNA gene expression-based stemness index (mRNAsi) and a DNA methylation-based stemness index (mDNAsi) were both calculated through one-class logistic regression. By applying univariate Cox regression analysis, we found that the mRNAsi and the mDNAsi correlated significantly with overall survival. Functional prediction analyses were used to characterize implicated genes and their degree of involvement as network hubs through protein-protein interaction analysis, and Spearman's rank correlation coefficient test was used to assess the relationship between hub genes and indices for stemness. The mRNAsi values for CGA and ICGC carcinoma samples correlated significantly with negative clinical characteristics and overall survival, whereas gene and protein-protein interaction analyses revealed that SNAP25, KPT19, GABBR1, and EPCAM were negatively associated with clinical mDNAsi scores. Collectively, the data suggest that our new stemness model based on related genes may predict patient prognoses.

Age-related trends in lipid levels: a large-scale cross-sectional study of the general Chinese population.

OBJECTIVES: This study aimed to investigate the dynamic trends in total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels with ageing. DESIGN: A Chinese population-based cross-sectional study. SETTING: A physical examination centre of a general hospital. PARTICIPANTS: Adult subjects (178 167: 103 461 men and 74 706 women) without a known medical history or treatments that affect lipid metabolism. MAIN OUTCOME MEASURES: Dynamic trends in the above-mentioned lipid parameters with ageing were explored; turning points of age were established using age stratification and validated by fitted multivariate linear regression modelling. RESULTS: Age was found to be an independent factor extensively associated with lipid levels in both sexes when adjusted for serum glucose, body mass index, lifestyle, drinking and smoking. Age was positively associated with TC, logarithm-transformed TG (LnTG) and LDL-C levels in men ≤40, ≤40 and ≤60 years old (yo) and in women ≤60, ≤70 and ≤60 yo, respectively. Conversely, age correlated negatively with TC, LnTG and LDL-C levels in men ≥61, ≥41 and ≥61 yo and in women ≥61, ≥71 and ≥61 yo, respectively. TC, TG and LDL-C levels in women were initially lower than those in men but surpassed those in men in 51-55, 61-65 and 51-55 yo age groups. The trends in HDL-C levels with age were relatively irregular, although HDL-C levels in women were higher than in men for all age groups. CONCLUSIONS: The definition of dyslipidaemia, the atherosclerotic cardiovascular disease risk assessment and the initiation/goals of statin therapy should fully consider age-related trends in lipid levels and sex differences.

γ-Oryzanol mitigates oxidative stress and prevents mutant SOD1-Related neurotoxicity in Drosophila and cell models of amyotrophic lateral sclerosis.

Oxidative stress plays a critical role in mutant copper/zinc superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by selective loss of motor neurons. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of ALS. The aim of the present study is to investigate the neuroprotective effects of γ-oryzanol (Orz) and elucidate its relevant molecular mechanisms in mutant hSOD1-linked Drosophila and cell models of ALS. Orz treatment provided neuroprotection in flies with expression of hSOD1-G85R in motor neurons, as demonstrated by the prolonged survival, improvement of motor deficits, reduced oxidative damage and regulated redox homeostasis when compared with those in controls. Moreover, Orz significantly decreased neuronal apoptosis and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLC) antioxidant pathway via activating Akt in hSOD1-G93A-expressing NSC-34 cells. In addition, our results showed that both in vivo and in vitro, Akt served as an upstream regulator of signal transducers and activators of transcription (Stat) 3 stimulated by Orz, which further increased the level of another anti-oxidative stress factor heat-shock protein 70 (HSP70). Altogether, these findings provide evidence that Orz has potential neuroprotective effects that may be beneficial in the treatment of ALS disease with SOD1 mutations.

Neuroprotection by urate on the mutant hSOD1-related cellular and Drosophila models of amyotrophic lateral sclerosis: Implication for GSH synthesis via activating Akt/GSK3ß/Nrf2/GCLC pathways.

Oxidative stress has been considered as a principal mechanism of motor neuron death in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease which could be caused by dominant mutations in an antioxidant enzyme superoxide dismutase-1 (SOD1). The aim of the present study was to investigate the potential neuroprotective effects and mechanisms of urate, an important endogenous antioxidant and a biomarker of favorable ALS progression rates, in the mutant human SOD1-related cellular and Drosophila models of ALS. Our results showed that urate treatment provided neuroprotective effects as confirmed by enhanced survival, attenuated motor impairments, reduced oxidative damage and increased antioxidant defense in hSOD1-G85R-expressing Drosophila models of ALS. In vitro studies, we demonstrated that urate protected motor neurons (NSC-34 cells) against hSOD1-G93A-induced cell damage and apoptosis by decreasing reactive oxygen specials (ROS) production and oxidative damage. Moreover, urate markedly increased the expression and activation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2-targeted antioxidant gene glutathione cysteine ligase catalytic subunit (GCLC) expression and glutathione (GSH) synthesis by upregulating Akt/GSK3ß pathway. Furthermore, the inhibition of Akt pathway with LY294002 abolished urate-mediated elevation of GSH synthesis and neuroprotective effects both in vivo and in vitro. Overall, these results suggested that, in addition to its direct scavenging of ROS, urate markedly enhanced GSH expression by activating Akt/GSK3ß/Nrf2/GCLC pathway, and thus offering neuroprotective effects on motor neurons against oxidative stress.

Spy1, a unique cell cycle regulator, alters viability in ALS motor neurons and cell lines in response to mutant SOD1-induced DNA damage.

Increasing evidence indicates that DNA damage and p53 activation play major roles in the pathological process of motor neuron death in amyotrophic lateral sclerosis (ALS). Human SpeedyA1 (Spy1), a member of the Speedy/Ringo family, enhances cell proliferation and promotes tumorigenesis. Further studies have demonstrated that Spy1 promotes cell survival and inhibits DNA damage-induced apoptosis. We showed that the Spy1 expression levels were substantially decreased in ALS motor neurons compared with wild-type controls both in vivo and in vitro by qRT-PCR, western blotting, and Immunoassay tests. In addition, we established that over-expression of human SOD1 mutant G93A led to a decreased expression of Spy1. Furthermore, DNA damage response was activated in SOD1G93A-transfected cells (mSOD1 cells). Moreover, decreased Spy1 expression reduced cell viability and further activated the DNA damage response in mSOD1 cells. In contrast, increased Spy1 expression improved cell viability and inhibited the DNA damage response in mSOD1 cells. These results suggest that Spy1 plays a protective role in ALS motor neurons. Importantly, these findings provide a novel direction for therapeutic options for patients with ALS as well as for trial designs, such as investigating the role of oncogenic proteins in ALS.

Astrocyte elevated gene-1 is a novel regulator of astrogliosis and excitatory amino acid transporter-2 via interplaying with nuclear factor-κB signaling in astrocytes from amyotrophic lateral sclerosis mouse model with hSOD1G93A mutation.

AEG-1 has received extensive attention on cancer research. However, little is known about its roles in astrogliosis of Amyotrophic lateral sclerosis (ALS). In this study, we detected AEG-1 expression in hSOD1G93A-positive (mut-SOD1) astrocytes and wild type (wt-SOD1) astrocytes, and intend to elucidate its potential functions in ALS related astrogliosis and the always accompanied dysregulated glutamate clearance. Results showed elevated protein and mRNA levels of AEG-1 in mut-SOD1 astrocytes; Also, NF-κB signaling pathway related proteins and inflammatory cytokines were upregulated in mut-SOD1 astrocytes; AEG-1 knockdown attenuated astrocytes proliferation and pro-inflammatory release; also we found that AEG-1 silence inhibited translocation of p65 from cytoplasma to nuclear, which was associated with inhibited NF-κB signaling. Besides, excitatory amino acid transporter-2 (EAAT2) expression levels were significantly decreased, accompanied by impaired glutamate clearance ability, in mut-SOD1 astrocytes; yin yang 1 (YY1), a transcriptional inhibitor for EAAT2, increased in nucleus of mut-SOD1 astrocytes. AEG-1 silence inhibited translocation of YY1 to nucleus, increased EAAT2 expression levels, and enhanced astrocytic ability of glutamate clearance, ultimately exerted the neuronal protection. Findings from this study implicate potential function of AEG-1 in mut-SOD1 related astrogliosis and the accompanied excitatory cytotoxic mechanism in ALS.

α-Lipoic acid attenuates oxidative stress and neurotoxicity via the ERK/Akt-dependent pathway in the mutant hSOD1 related Drosophila model and the NSC34 cell line of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative disease with a progressive loss of motor neurons in the central nervous system (CNS). However, there are unsolved problems with the therapies for this disease. α-Lipoic acid (LA) is a natural, universal antioxidant capable of scavenging hydroxyl radicals as well as regenerating a series of antioxidant enzymes that has been widely used in clinical settings. This study aimed to evaluate the antioxidant and neuroprotective effects of LA in ALS cell and Drosophila models with mutant G85R and G93A hSOD1 genes. The biological effects of LA and the protein levels of several antioxidant factors were examined, as were those of phospho-Akt and phospho-ERK. Furthermore, specific inhibitors of the PI3K/Akt and MEK/ERK signaling pathways were used to analyze their effects on LA-induced antioxidant expression in vivo and in vitro. Evidences showed that the mutant hSOD1 resulted in the increased oxidative stress, abnormal antioxidant signaling and pathological behaviors in motor performance and survival compared with non-mutant hSOD1 models, treatment with LA improved motor activity and survival in transgenic flies, prevented NSC34 cells from mutant hSOD1 or H2O2 induced decreased antioxidant enzymes as well as increased ROS levels. In addition, LA regulated the expression levels of antioxidant proteins in a dose- and periodical time-dependent manner, which might be mediated by ERK/Akt pathway activation and independent from the mutant hSOD1 gene. Our observations suggest that LA exerts strong and positive antioxidant and neuroprotective effects through the activation of the ERK-Akt pathway in hSOD1 ALS models.

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.

BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.

FRK suppresses the proliferation of human glioma cells by inhibiting cyclin D1 nuclear accumulation.

The Fyn related kinase (FRK) is a noteworthy member of the Src non-receptor tyrosine kinase family for its distinctive tumor suppressive function. Recently, we have shown that FRK plays a protective role against the progression of glioma by suppressing cell migration and invasion. However, it is unclear whether the cell growth of glioma is also regulated by FRK and by which mechanism FRK alters its specific biological functions. In the current study, we found that FRK over-expression significantly suppressed the proliferation of glioma cells. In contrast, FRK knockdown by siRNA promoted glioma cell growth. In addition, FRK over-expression caused G1 phase arrest as well as apoptosis of glioma cells. Further investigation disclosed that FRK-induced G1 arrest was accompanied by down-regulation of hyperphosphorylated retinoblastoma protein (pRb), which led to the consequent suppression of E2F1. More importantly, we found that over-expression of FRK inhibited proper cyclin D1 accumulation in the nucleus of proliferating cells. Taken together, our results demonstrate a combined mechanism for the anti-proliferative effects of FRK by inhibiting cyclin D1 nucleus accumulation and pRb phosphorylation in glioma cells.

Polypyrrole-enveloped Pd and Fe3O4 nanoparticle binary hollow and bowl-like superstructures as recyclable catalysts for industrial wastewater treatment.

Metal and metal-oxide nanoparticles (NPs) are promising catalysts for dye degradation in wastewater treatment despite the challenges of NP recovery and recycling. In this study, water-dispersible NP superstructures with spherical morphology were constructed from hydrophobic Pd and Fe3O4 NPs by virtue of the oil droplets in an oil-in-water microemulsion as templates. Control of the evaporation rate of organic solvents in the oil droplets produces solid, hollow, and bowl-like superstructures. The component Fe3O4 and in particular Pd NPs can catalyze H2O2 degradation to create hydroxyl radicals and therewith degrade various dyes, and the magnetic Fe3O4 NPs also permit recycling of the superstructures with a magnet. Because the hollow and bowl-like superstructures increase the contact area of the NPs with their surroundings in comparison to solid superstructures, the catalytic activity is greatly enhanced. To improve the structural stability, the superstructures were further enveloped with a thin polypyrrole (PPy) shell, which does not weaken the catalytic activity. Because the current method is facile and feasible to create recyclable catalysts, it will promote the practicability of NP catalysts in treating industrial polluted water.