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At least 1,459 records · Page 81

Climate Change Projection in the Twenty-First Century Simulated by NIMS-KMA CMIP6 Model Based on New GHGs Concentration Pathways

Abstract The National Institute of Meteorological Sciences-Korea Meteorological Administration (NIMS-KMA) has participated in the Coupled Model Inter-comparison Project (CMIP) and provided long-term simulations using the coupled climate model. The NIMS-KMA produces new future projections using the ensemble mean of KMA Advanced Community Earth system model (K-ACE) and UK Earth System Model version1 (UKESM1) simulations to provide scientific information of future climate changes. In this study, we analyze four experiments those conducted following the new shared socioeconomic pathway (SSP) based scenarios to examine projected climate change in the twenty-first century. Present day (PD) simulations show high performance skill in both climate mean and variability, which provide a reliability of the climate models and reduces the uncertainty in response to future forcing. In future projections, global temperature increases from 1.92 °C to 5.20 °C relative to the PD level (1995–2014). Global mean precipitation increases from 5.1% to 10.1% and sea ice extent decreases from 19% to 62% in the Arctic and from 18% to 54% in the Antarctic. In addition, climate changes are accelerating toward the late twenty-first century. Our CMIP6 simulations are released to the public through the Earth System Grid Federation (ESGF) international data sharing portal and are used to support the establishment of the national adaptation plan for climate change in South Korea.

54 ENVIRONMENTAL SCIENCES↗

Gas-Phase Oxidation via Ion/Ion Reactions: Pathways and Applications

Here, we provide an overview of pathways available upon the gas-phase oxidation of peptides and DNA via ion/ion reactions and explore potential applications of these chemistries. The oxidation of thioethers (i.e., methionine residues and S-alkyl cysteine residues), disulfide bonds, S-nitrosylated cysteine residues, and DNA to the [M+H+O]{sup +} derivative via ion/ion reactions with periodate and peroxymono-sulfate anions is demonstrated. The oxidation of neutral basic sites to various oxidized structures, including the [M+H+O]{sup +}, [M–H]{sup +}, and [M–H–NH{sub 3}]{sup +} species, via ion/ion reactions is illustrated and the oxidation characteristics of two different oxidizing reagents, periodate and persulfate anions, are compared. Lastly, the highly efficient generation of molecular radical cations via ion/ion reactions with sulfate radical anion is summarized. Activation of the newly generated molecular radical peptide cations results in losses of various neutral side chains, several of which generate dehydroalanine residues that can be used to localize the amino acid from which the dehydroalanine was generated. The chemistries presented herein result in a diverse range of structures that can be used for a variety of applications, including the identification and localization of S-alkyl cysteine residues, the oxidative cleavage of disulfide bonds, and the generation of molecular radical cations from even-electron doubly protonated peptides. .

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Structure of Rhizobium sp. 4-9 histamine dehydrogenase and analysis of the electron transfer pathway to an abiological electron acceptor

Histamine dehydrogenase from the gram-negative bacterium Rhizobium sp. 4-9 (HaDHR) is a member of a small family of dehydrogenases containing a covalently attached FMN, and the only member so far identified to date that does not exhibit substrate inhibition. Here, in this study, we present the 2.1 Å resolution crystal structure of HaDHR. This new structure allowed for the identification of the internal electron transfer pathway to abiological ferrocene-based mediators. Alanine 437 was identified as the exit point of electrons from the Fe 4 S 4 cluster. The enzyme was modified with a Ser436Cys mutation to facilitate covalent attachment of a ferrocene moiety. When modified with Fc-maleimide, this new construct demonstrated direct electron transfer from the enzyme to a gold electrode in a histamine concentration-dependent manner without the need for any additional electron mediators.

59 BASIC BIOLOGICAL SCIENCES↗

Actinium–DOTA coordination in water from hybrid ML/MM: Structure, free energies, and water-exchange pathways

Quantitative simulation of trivalent ƒ-block chelates in water remains challenging because bonded and non-bonded force-field models make different approximations for coordination structure, exchange dynamics, and ion–ligand interactions in highly charged systems. Here, we develop a hybrid machine-learning/molecular-mechanics (ML/MM) framework for Ac 3+ –DOTA in explicit solvent by training an E(3)-equivariant neural network potential (MACELES) on mechanically embedded QM/MM data for Ac aquo and Ac–DOTA species and coupling it to NAMD 2.14 with particle-mesh Ewald electrostatics. Nanosecond ML/MM trajectories remain numerically stable and preserve chelate integrity, yielding a compact DOTA inner shell with an inner-sphere water coordination number of CN Ac,O w ≈ 1.7 arising from a dynamic equilibrium between one- and two-water states (37.5% and 59.9% of frames; three waters 2.5%). A 5 ns potential of mean force shows two low-lying basins at CN Ac,O w ≈ 1 and CN Ac,O w ≈ 2. DFT end-state free energies are consistent with the ML/MM profile, and DFT minimum-energy paths provide a qualitative electronic-structure reference for the observed basin connectivity. State-resolved kinetics reveal picosecond water-exchange pathways that couple hydration changes to transient DOTA arm fluctuations, and training-set comparisons show that temperature-matched Ac–DOTA data optimize energy/force accuracy while more diverse solvated data improve charge prediction. Overall, the present hybrid ML/MM model provides a practical description of Ac 3+ –DOTA hydration thermodynamics and short-time exchange behavior in explicit water at MD-like cost.

Actinium↗

On the various Cu-redox pathways and O 2 -mediated Bronsted-to-Lewis adsorbed-NH 3 redistribution under SCR half-cycle conditions

The Standard SCR reaction on Cu-SSZ-13 is a complex redox process facilitated by a reduction half cycle (RHC) and an oxidation half cycle (OHC). It is generally accepted that RHC requires the simultaneous presence of NO and NH 3 , while OHC requires both NO and O 2 ; however understanding of how these individual reactants impact the Cu redox cycle is limited. In this work, we provide experimental investigation of NO-only, NH 3 -only and NO+NH 3 RHC, and their relative rates. Simple kinetic models were developed to understand the dependance of NO-only and NH 3 -only RHC on Cu speciation. Various OHC routes including NO+O 2 and O 2 -only OHC, and a previously unreported H 2 O-mediated OHC pathway were also investigated. Detailed NH 3 temperature-programmed desorption studies showed that RHC selectively consumes NH 3 adsorbed on Lewis-acid sites, and that part of the remaining Bronsted-bound NH 3 moves to the Lewis-acid sites during subsequent OHC, thereby resulting in a repartitioning of adsorbed NH 3 .

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Electric-vehicle battery second-life and recycling pathways: How economics depend on chemistry, processing, and application

We assess the economics of repurposing and recycling electric vehicle (EV) batteries by estimating the maximum acquisition price repurposers and recyclers could pay for used EV packs across cathode chemistries, first-life conditions, second-life applications, and recycling processes. We develop a novel open-source process-based cost model of a UL-1974-certified repurposing facility and leverage battery degradation models to estimate the maximum acquisition price repurposers could pay for used EV batteries while producing second-life battery energy storage systems with life-adjusted costs equivalent to new systems. We compare these maximum price estimates to maximum prices for recyclers based on cost and revenue estimates from the EverBatt model. We find that repurposing is more economical than recycling for lithium iron phosphate (LFP) batteries, due to their relatively long life and low value materials; recycling is generally more economical than repurposing for lithium nickel cobalt aluminum oxide (NCA) batteries, due to their shorter life and higher value materials; and the economics for lithium nickel manganese cobalt oxide (NMC) batteries depend more heavily on first life retirement conditions and second life application intensity. These results suggest an overall strategy: reuse LFP, recycle NCA, and sort NMC into recycling or repurposing pathways based on state of health and second-life application.

25 ENERGY STORAGE↗

Reaction of BCl 3 with H- and Cl-terminated Si(100) as a pathway for selective, monolayer doping through wet chemistry

The reaction of boron trichloride with the H and Cl-terminated Si(100) surfaces was investigated to understand the interaction of this molecule with the surface for designing wet-chemistry based silicon surface doping processes using a carbon- and oxygen-free precursor. The process was followed with X-ray photoelectron spectroscopy (XPS). Within the reaction conditions investigated, the reaction is highly effective on Cl-Si(100) for temperatures below 70°C, at which point both surfaces react with BCl$_3$. The XPS investigation followed the formation of a B 1s peak at 193.5 eV corresponding to (B-O)$_x$ species. Even the briefest exposure to ambient conditions lead to hydroxylation of surface borochloride species. However, the Si 2p signature at 102 eV allowed for a confirmation of the formation of a direct Si-B bond. Density functional theory was utilized to supplement the analysis and identify possible major surface species resulting from these reactions. This work provides a new pathway to obtain a functionalized silicon surface with a direct Si-B bond that can potentially be exploited as a means of selective, ultra-shallow, and supersaturated doping.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-κB-dependent pathway

Highlights: •IL-6 could induce PON1 gene expression. •IL-6 increased NF-κB protein expression and NF-κB-p50 and -p65 subunits nuclear translocation. •IL-6-induced PON1 up-regulation was through an AKT/NF-κB pathway. -- Abstract: The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro-inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-α and IL-1β, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-induced PON1 expression occurred at the transcriptional level. Increase of IκB kinase activity and IκB phosphorylation, and reduction of IκB protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-κB-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-κB. Furthermore, pharmacological inhibition of NF-κB activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/IκB/NF-κB signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-κB signaling axis in human hepatocyte-derived HepG2 cell line.

60 APPLIED LIFE SCIENCES↗

Identification of methyl violet 2B as a novel blocker of focal adhesion kinase signaling pathway in cancer cells

Highlights: •FAK signaling cascade in cancer cells is profoundly inhibited by methyl violet 2B. •Methyl violet 2B identified by virtual screening is a novel allosteric FAK inhibitor. •Methyl violet 2B possesses extremely high kinase selectivity. •Methyl violet 2B suppresses strongly the proliferation of cancer cells. •Methyl violet 2B inhibits focal adhesion, invasion and migration of cancer cells. -- Abstract: The focal adhesion kinase (FAK) signaling cascade in cancer cells was profoundly inhibited by methyl violet 2B identified with the structure-based virtual screening. Methyl violet 2B was shown to be a non-competitive inhibitor of full-length FAK enzyme vs. ATP. It turned out that methyl violet 2B possesses extremely high kinase selectivity in biochemical kinase profiling using a large panel of kinases. Anti-proliferative activity measurement against several different cancer cells and Western blot analysis showed that this substance is capable of suppressing significantly the proliferation of cancer cells and is able to strongly block FAK/AKT/MAPK signaling pathways in a dose dependent manner at low nanomolar concentration. Especially, phosphorylation of Tyr925-FAK that is required for full activation of FAK was nearly completely suppressed even with 1 nM of methyl violet 2B in A375P cancer cells. To the best of our knowledge, it has never been reported that methyl violet possesses anti-cancer effects. Moreover, methyl violet 2B significantly inhibited FER kinase phosphorylation that activates FAK in cell. In addition, methyl violet 2B was found to induce cell apoptosis and to exhibit strong inhibitory effects on the focal adhesion, invasion, and migration of A375P cancer cells at low nanomolar concentrations. Taken together, these results show that methyl violet 2B is a novel, potent and selective blocker of FAK signaling cascade, which displays strong anti-proliferative activities against a variety of human cancer cells and suppresses adhesion/migration/invasion of tumor cells.

60 APPLIED LIFE SCIENCES↗

Inhibition of fatty acid synthase suppresses U-2 OS cell invasion and migration via downregulating the activity of HER2/PI3K/AKT signaling pathway in vitro

Highlights: •We investigate the relationship between FASN and HER2 or p-HER2 by IHC in OS tissues. •We construct FASN-specific RNAi plasmid. •Inhibiting FASN down-regulates HER2/PI3K/AKT cell signaling in U-2 OS. •Inhibiting FASN blocks U-2 OS cell invasion and migration. -- Abstract: FASN plays an important role in the malignant phenotype of various tumors. Our previous studies show that inhibition FASN could induce apoptosis and inhibit proliferation in human osteosarcoma (OS) cell in vivo and vitro. The aim in this study was to investigate the effect of inhibition FASN on the activity of HER2/PI3K/AKT axis and invasion and migration of OS cell. The expression of FASN, HER2 and p-HER2(Y1248) proteins was detected by immunohistochemistry in OS tissues from 24 patients with pulmonary metastatic disease, and the relationship between FASN and p-HER2 as well as HER2 was investigated. The results showed that there was a positive correlation between FASN and HER2 as well as p-HER2 protein expression. The U-2 OS cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid. FASN mRNA was measured by RT-PCR. Western blot assays was performed to examine the protein expression of FASN, HER2, p-HER2(Y1248), PI3K, Akt and p-Akt (Ser473). Migration and invasion of cells were investigated by wound healing and transwell invasion assays. The results showed that the activity of HER2/PI3K/AKT signaling pathway was suppressed by inhibiting FASN. Meanwhile, the U-2OS cells migration and invasion were also impaired by inhibiting the activity of FASN/HER2/PI3K/AKT. Our results indicated that inhibition of FASN suppresses OS cell invasion and migration via down-regulation of the “HER2/PI3K/AKT” axis in vitro. FASN blocker may be a new therapeutic strategy in OS management.

60 APPLIED LIFE SCIENCES↗

Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α.

60 APPLIED LIFE SCIENCES↗

22(R)-hydroxycholesterol and pioglitazone synergistically decrease cholesterol ester via the PPARγ–LXRα–ABCA1 pathway in cholesterosis of the gallbladder

Highlights: • Cholesterosis is a metabolic disease characterized by excessive lipid droplets. • Lipid droplet efflux is mediated by the ABCA1 transporter. • 22(R)-hydroxycholesterol can activate LXRα and up-regulate ABCA1. • Pioglitazone up-regulates ABCA1 in a PPARγ–LXRα–ABCA1-dependent manner. • 22(R)-hydroxycholesterol and pioglitazone synergistically decrease lipid droplets. - Abstract: Cholesterosis is a disease of cholesterol metabolism characterized by the presence of excessive lipid droplets in the cytoplasm. These lipid droplets are mainly composed of cholesterol esters derived from free cholesterol. The removal of excess cholesterol from gallbladder epithelial cells (GBECs) is very important for the maintenance of intracellular cholesterol homeostasis and the preservation of gallbladder function. Several lines of evidence have indicated that the activation of either peroxisome proliferator-activated receptor gamma (PPARγ) or liver X receptor α (LXRα) relates to cholesterol efflux. While pioglitazone can regulate the activation of PPARγ, 22(R)-hydroxycholesterol can activate LXRα and is a metabolic intermediate in the biosynthesis of steroid hormones. However, the effect of 22(R)-hydroxycholesterol in combination with pioglitazone on cholesterosis of the gallbladder is unclear. GBECs were treated with pioglitazone, 22(R)-hydroxycholesterol or PPARγ siRNA followed by Western blot analysis for ATP-binding cassette transporter A1 (ABCA1), PPARγ and LXRα. Cholesterol efflux to apoA-I was determined, and Oil Red O staining was performed to monitor variations in lipid levels in treated GBECs. Our data showed that 22(R)-hydroxycholesterol can modestly up-regulate LXRα while simultaneously increasing ABCA1 by 56%. The combination of 22(R)-hydroxycholesterol and pioglitazone resulted in a 3.64-fold increase in ABCA1 expression and a high rate of cholesterol efflux. Oil Red O staining showed an obvious reduction in the lipid droplets associated with cholesterosis in GBECs. In conclusion, the present findings indicate that the anti-lipid deposition action of 22(R)-hydroxycholesterol combined with pioglitazone involves the activation of the PPARγ–LXRα–ABCA1 pathway, increased ABCA1 expression and the efflux of cholesterol from GBECs. Thus, 22(R)-hydroxycholesterol synergistically combined with pioglitazone to produce a remarkable effect on lipid deposition in cholesterosis GBECs.

60 APPLIED LIFE SCIENCES↗

Long-term low-dose α-particle enhanced the potential of malignant transformation in human bronchial epithelial cells through MAPK/Akt pathway

Highlights: • Multi-exposures of 25 mGy α-ray enhanced cell proliferation, adhesion, and invasion. • MAPK/Akt but not JNK/P66 was positively correlated with cell invasive phenotypes. • LDR of α-irradiation triggers cell malignant transformation through MAPK/Akt. - Abstract: Since the wide usage of ionizing radiation, the cancer risk of low dose radiation (LDR) (<0.1 Gy) has become attractive for a long time. However, most results are derived from epidemiologic studies on atomic-bomb survivors and nuclear accidents surrounding population, and the molecular mechanism of this risk is elusive. To explore the potential of a long-term LDR-induced malignant transformation, human bronchial epithelial cells Beas-2B were fractionally irradiated with 0.025 Gy α-particles for 8 times in total and then further cultured for 1–2 months. It was found that the cell proliferation, the abilities of adhesion and invasion, and the protein expressions of p-ERK, p-Akt, especially p-P38 were not only increased in the multiply-irradiated cells but also in their offspring 1–2 months after the final exposure, indicating high potentiality of cell malignant transformation. On opposite, the expressions of p-JNK and p-P66 were diminished in the subcultures of irradiated cells and thus may play a role of negative regulation in canceration. When the cells were transferred with p38 siRNA, the LDR-induced enhancements of cell adhesion and invasion were significantly reduced. These findings suggest that long-term LDR of α-particles could enhance the potential of malignant transformation incidence in human bronchial epithelial cells through MAPK/Akt pathway.

60 APPLIED LIFE SCIENCES↗

RFP tags for labeling secretory pathway proteins

Highlights: • Membrane protein Orai1 can be used to report the fusion properties of RFPs. • Artificial puncta are affected by dissociation constant as well as pKa of RFPs. • Among tested RFPs mOrange2 is the best choice for secretory protein labeling. - Abstract: Red fluorescent proteins (RFPs) are useful tools for live cell and multi-color imaging in biological studies. However, when labeling proteins in secretory pathway, many RFPs are prone to form artificial puncta, which may severely impede their further uses. Here we report a fast and easy method to evaluate RFPs fusion properties by attaching RFPs to an environment sensitive membrane protein Orai1. In addition, we revealed that intracellular artificial puncta are actually colocalized with lysosome, thus besides monomeric properties, pKa value of RFPs is also a key factor for forming intracellular artificial puncta. In summary, our current study provides a useful guide for choosing appropriate RFP for labeling secretory membrane proteins. Among RFPs tested, mOrange2 is highly recommended based on excellent monomeric property, appropriate pKa and high brightness.

60 APPLIED LIFE SCIENCES↗

Sensitization of cancer cells to radiation by selenadiazole derivatives by regulation of ROS-mediated DNA damage and ERK and AKT pathways

Highlights: • Selenadiazole derivatives could be used as an effective and low toxic sensitizer for radiotherapy. • Selenadiazole derivatives enhances radiation-induced growth inhibition on A375 cells through induction of G2/M arrest. • ROS-mediated signaling pathways play important roles in radiosensitization of selenadiazole derivatives. - Abstract: X-ray-based radiotherapy represents one of the most effective ways in treating human cancers. However, radioresistance and side effect remain as the most challenging issue. This study describes the design and application of novel selenadiazole derivatives as radiotherapy sensitizers to enhance X-ray-induced inhibitory effects on A375 human melanoma and Hela human cervical carcinoma cells. The results showed that, pretreatment of the cells with selenadiazole derivatives dramatically enhance X-ray-induced growth inhibition and colony formation. Flow cytometry analysis indicates that the sensitization by selenadiazole derivatives was mainly caused by induction of G2/M cell cycle arrest. Results of Western blotting demonstrated that the combined treatment-induced A375 cells growth inhibition was achieved by triggering reactive oxygen species-mediated DNA damage involving inactivation of AKT and MAPKs. Further investigation revealed that selenadiazole derivative in combination with X-ray could synergistically inhibit the activity of thioredoxin reductase-1 in A375 cells. Taken together, these results suggest that selenadiazole derivatives can act as novel radiosensitizer with potential application in combating human cancers.

60 APPLIED LIFE SCIENCES↗

Cadmium induces vascular permeability via activation of the p38 MAPK pathway

Highlights: • Low-dose cadmium (Cd) induces vascular hyper-permeability. • p38 MAPK mediates Cd-induced disruption of endothelial cell barrier function. • SB203850 inhibits Cd-induced membrane dissociation of VE-cadherin and β-catenin. • SB203850 reduces Cd-induced expression and secretion of TNF-α. - Abstract: The vasculature of various organs is a targeted by the environmental toxin, cadmium (Cd). However, mechanisms leading to pathological conditions are poorly understood. In the present study, we examined the effect of cadmium chloride (CdCl{sub 2}) on human umbilical vein endothelial cells (HUVECs). At 4 μM, CdCl{sub 2} induced a hyper-permeability defect in HUVECs, but not the inhibition of cell growth up to 24 h. This effect of CdCl{sub 2} was dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. The p38 MAPK inhibitor SB203850 suppressed the CdCl{sub 2}-induced alteration in trans-endothelial electrical resistance in HUVEC monolayers, a model measurement of vascular endothelial barrier integrity. SB203850 also inhibited the Cd-induced membrane dissociation of vascular endothelial (VE) cadherin and β-catenin, the important components of the adherens junctional complex. In addition, SB203850 reduces the Cd-induced expression and secretion of tumor necrosis factor α (TNF-α). Taken together, our findings suggest that Cd induces vascular hyper-permeability and disruption of endothelial barrier integrity through stimulation of p38 MAPK signaling.

60 APPLIED LIFE SCIENCES↗

Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway

Highlights: • Aloperine has anti-nociceptive effects on neuropathic pain induced CCI. • Aloperine reduces ROS in neuropathic pain mice. • Aloperine down-regulates the expression of NF-κB and its downstream pro-inflammatory cytokines in neuropathic pain mice. - Abstract: Objective: To investigate whether aloperine (ALO) has antinociceptive effects on neuropathic pain induced by chronic constriction injury, whether ALO reduces ROS against neuropathic pain, and what are the mechanisms involved in ALO attenuated neuropathic pain. Methods: Mechanical and cold allodynia, thermal and mechanical hyperalgesia and spinal thermal hyperalgesia were estimated by behavior methods such as Von Frey filaments, cold-plate, radiant heat, paw pressure and tail immersion on one day before surgery and days 7, 8, 10, 12 and 14 after surgery, respectively. In addition, T-AOC, GSH-PX, T-AOC and MDA in the spinal cord (L4/5) were measured to evaluate anti-oxidation activity of ALO on neuropathic pain. Expressions of NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the spinal cord (L4/5) were analyzed by using Western blot. Results: Administration of ALO (80 mg/kg and 40 mg/kg, i.p.) significantly increased paw withdrawal threshold, paw pressure, paw withdrawal latencies, tail-curling latencies, T-AOC, GSH-PX and T-SOD concentration, reduced the numbers of paw lifts and MDA concentration compared to CCI group. ALO attenuated CCI induced up-regulation of expressions of NF-κB, TNF-α, IL-6, IL-1β at the dose of 80 mg/kg (i.p.). Pregabalin produced similar effects serving as positive control at the dose of 10 mg/kg (i.p.). Conclusion: ALO has antinociceptive effects on neuropathic pain induced by CCI. The antinociceptive effects of ALO against neuropathic pain is related to reduction of ROS, via suppression of NF-κB pathway.

60 APPLIED LIFE SCIENCES↗

Thymosin β4 induces invasion and migration of human colorectal cancer cells through the ILK/AKT/β-catenin signaling pathway

Highlights: • Tβ4 is overexpressed in human colorectal cancer cells. • The overexpression of Tβ4 is correlated with stage of colorectal cancer. • Tβ4 stimulates cell adhesion, invasion, migration and EMT. • Tβ4 activates the ILK/AKT/β-catenin signaling pathway. - Abstract: Thymosin β4 (Tβ4) is a 43-amino-acid peptide involved in many biological processes. However, the precise molecular signaling mechanism(s) of Tβ4 in cell invasion and migration remain unclear. In this study, we show that Tβ4 was significantly overexpressed in colorectal cancer tissues compared to adjacent normal tissues and high levels of Tβ4 were correlated with stage of colorectal cancer, and that Tβ4 expression was associated with morphogenesis and EMT. Tβ4-upregulated cancer cells showed increased adhesion, invasion and migration activity, whereas Tβ4-downregulated cells showed decreased activities. We also demonstrated that Tβ4 interacts with ILK, which promoted the phosphorylation and activation of AKT, the phosphorylation and inactivation of GSK3β, the expression and nuclear localization of β-catenin, and integrin receptor activation. These results suggest that Tβ4 is an important regulator of the ILK/AKT/β-catenin/Integrin signaling cascade to induce cell invasion and migration in colorectal cancer cells, and is a potential target for cancer treatment.

60 APPLIED LIFE SCIENCES↗