Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound ...injury model (STAB) display aberrant cellular gamma‐aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO‐B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO‐B, a GABA‐producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO‐B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO‐B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by‐products of the MAO‐B action, H2O2, but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar‐forming astrogliosis—the recently developed reversible MAO‐B inhibitor, KDS2010, and an H2O2 scavenger, crisdesalazine (AAD‐2004). Our results implicate that inhibiting MAO‐B activity has dual beneficial effects in preventing astrogliosis and scar‐formation under brain injury, and that the MAO‐B/H2O2 pathway can be a useful therapeutic target with a high clinical potential.
MAIN POINTS:
MAO‐B and H2O2 regulate the scar‐forming reactive astrocytes in brain injury model.
A reversible MAO‐B inhibitor, KDS2010, and a H2O2 scavenger, crisdesalazine (AAD‐2004), are potent pharmacological tools to attenuate scar‐forming astrogliosis.
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•Tetralin as an H-donor promotes the reactivity of asphaltenes.•Tetralin reduces coke and gas formation in hydrocracking of pitch.•Dispersed MoS2 catalyst coupled with H-donor ...improves pitch HCK performance.
The effects of tetralin as an H-donor on the reactivity of asphaltenes in a petroleum pitch were investigated under thermal cracking or catalytic hydrocracking conditions at 693 K and 10.0 MPa N2 or H2. Reaction temperatures, pressures, and tetralin contents were varied to examine the reactivity of asphaltenes. Thermal cracking of the petroleum pitch led to a considerable amount of coke formation, close to 53.7 wt%, but the addition of tetralin reduced the coke formation down to 23.6 wt%. The coke formation was considerably reduced to 10.3 wt% in the catalytic hydrocracking condition, and was not formed in the presence of tetralin. Kinetic studies on the catalytic hydrocracking of petroleum pitch in the absence or presence of tetralin demonstrated that the addition of tetralin, showing an increase in the hydrogen transfer capacity, contribute to the marked performance of hydrocracking of the petroleum pitch in the presence of dispersed MoS2 catalyst.
In this study, we utilized processed edible commercial wheat and oat flours to synthesize highly fluorescent carbon dots using green hydrothermal synthesis. The as‐synthesized carbon quantum dots ...(CQDs) were characterized using UV‐vis spectrophotometry, photoluminescence spectrophotometry, high‐resolution transmission electron microscopy, and Fourier transform infrared spectroscopy. The synthesized wheat‐CQDs (W‐CQDs) and oat‐CQDs (O‐CQDs) had monodispersed spherical shapes with average sizes of 3–8 and 5–10 nm, respectively, and exhibited strong fluorescence intensity and excitation‐dependent photoluminescence. The W‐CQDs and O‐CQDs were highly dispersed in aqueous solutions and exhibited bright green and blue fluorescence, respectively, under UV light (λex=380 and 370 nm). Both CQDs contained abundant functional groups, including amino, hydroxyl, and carboxyl groups, which may play a major role in biological applications. The W‐CQDs and O‐CQDs showed good free‐radical scavenging capacity in the 2,2‐diphenylpicrylhydrazyl (DPPH) and H2O2 assays. The anti‐inflammatory activities of W‐CQDs and O‐CQDs were more effective than that of the standard, with EC50 values of 1.8 and 1.3 mg/mL, respectively, in the protein denaturation assay. Additionally, the CQDs exhibited low cytotoxicity toward NIH3T3 fibroblast and human HeLa cervical cancer cells when treated with a 5‐mg/mL concentration. Therefore, green‐synthesized W‐CQDs and O‐CQDs are easily available, less cytotoxic, and applicable to therapeutic and cell nanocarrier purposes.
Wheat and Oat flours extract used for the synthesis of CQDs by sustainable hydrothermal method. The synthesized W‐CQDs and O‐CQDs exhibits potent optical properties. W‐CQDs and O‐CQDs are low toxicity against NIH3T3 cells and HeLa cancer cells. The synthesized CQDs have good anti‐oxidant and anti‐inflammatory activity in in‐vitro assays.
Probiotics in livestock feed supplements are considered a replacement for antibiotics that enhance gastrointestinal immunity. Although bacterial cell wall components have been proposed to be ...associated with probiotic function, little evidence demonstrates that they are responsible for probiotic functions in livestock. The present study demonstrated that lipoteichoic acid (LTA) of
(Lp.LTA) confers anti-inflammatory responses in porcine intestinal epithelial cell line, IPEC-J2. A synthetic analog of viral double-stranded RNA, poly I:C, dose-dependently induced IL-8 production at the mRNA and protein levels in IPEC-J2 cells. Lp.LTA, but not lipoprotein or peptidoglycan from
, exclusively suppressed poly I:C-induced IL-8 production. Compared with LTAs from other probiotic
strains including
,
, and
GG, Lp.LTA had higher potential to suppress poly I:C-induced IL-8 production. Dealanylated or deacylated Lp.LTA did not suppress poly I:C-induced IL-8 production, suggesting that D-alanine and lipid moieties in the Lp.LTA structure were responsible for the inhibition. Furthermore, Lp.LTA attenuated the phosphorylation of ERK and p38 kinase as well as the activation of NF-κB, resulting in decreased IL-8 production. Taken together, these results suggest that Lp.LTA acts as an effector molecule to inhibit viral pathogen-induced inflammatory responses in porcine intestinal epithelial cells.
Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The ...Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
Sensory discrimination is essential for survival. However, how sensory information is finely controlled in the brain is not well defined. Here, we show that astrocytes control tactile acuity via ...tonic inhibition in the thalamus. Mechanistically, diamine oxidase (DAO) and the subsequent aldehyde dehydrogenase 1a1 (Aldh1a1) convert putrescine into GABA, which is released via Best1. The GABA from astrocytes inhibits synaptically evoked firing at the lemniscal synapses to fine-tune the dynamic range of the stimulation-response relationship, the precision of spike timing, and tactile discrimination. Our findings reveal a novel role of astrocytes in the control of sensory acuity through tonic GABA release.
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•Thalamic astrocytes synthesize GABA via DAO and Aldh1a1 to mediate tonic inhibition•Tonic GABA improves linearity and temporal fidelity of synaptically evoked TC firing•Astrocytic tonic GABA improves tactile discrimination performance
Kwak et al. report that astrocytes synthesize GABA using DAO and Aldh1a1 and release GABA through the Best1 channel to mediate tonic GABA in the thalamus. Astrocytic tonic GABA fine-tunes the dynamic range and precision of stimulation to response of TC firing, thus enhancing the performance of sensory discrimination of mice.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by abnormal movement, including slowed movements, shuffling gait, lack of balance, and tremor. Oxidative stress has been shown ...to play a decisive role in dopaminergic neuronal cell death in PD. The nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling pathway provides the main defense system against oxidative stress by inducing the expression of antioxidant enzyme genes. Direct interference in the Keap1-Nrf2 protein-protein interaction (PPI) has emerged as an effective strategy for Nrf2 activation. Therefore, we searched for novel Nrf2 activators that can disrupt Nrf2-Keap1 interaction by using a virtual screening approach and identified a potent Nrf2 activator, KKPA4026. KKPA4026 was confirmed to induce the expression of the Nrf2-dependent antioxidant enzymes heme oxygenase-1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase regulatory subunit, and NAD(P)H:quinone oxidoreductase 1 in BV-2 cells. Furthermore, KKPA4026 showed anti-inflammatory effects in an Nrf2-dependent manner. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, KKPA4026 effectively attenuated PD-associated behavioral deficits and protected dopaminergic neurons. In summary, we identified KKPA4026 as a novel Nrf2 activator and suggested that Nrf2 activation through interference with the Nrf2-Keap1 interaction may be effective for PD treatment.
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•Discovery of KKPA4026, a potent Nrf2 activator via interference with Keap1-Nrf2 interaction.•KKPA4026 induces Nrf2 nuclear translocation and upregulates the expression of Nrf2-dependent antioxidant enzymes.•KKPA4026 reduces the production of inflammatory mediators in an Nrf2-dependent manner.•KKPA4026 attenuates PD-associated motor deficits in MPTP-induced mouse model and protects dopaminergic neurons.
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•Reduction of Mo-Fe/MgO catalyst leads to high-yield carbon production.•Increasing reduction temperature leads to larger CNT diameter and higher crystallinity.•Increasing reduction ...hydrogen partial pressure (pH2) leads to larger CNT diameter.•Optimum reduction conditions (Temp, pH2, Time) of Mo-Fe/MgO catalyst for high quality CNT were found.
The effects of temperature, hydrogen partial pressure, and time in catalytic reduction step on carbon nanotube growth in a catalytic methane decomposition have been investigated for Mo-Fe/MgO catalysts. The results show that the reduction conditions of the catalyst affect the crystal structure of the metal formed on the catalyst surface and the growth mechanism of the generated carbon nanotubes. Both diameter distribution and crystallinity of the CNTs increased with the increase of reduction temperature in the range of 400 to 800 °C. The optimal reduction temperature with the maximum carbon yield was found to be 500 °C. The increase of hydrogen partial pressure and reduction time increased the CNT diameter distribution, and the optimal hydrogen partial pressure and reduction time with maximum carbon yield were found to be 0.1 atm, 60 min and 0.3 atm, 5 min, respectively. In the different combination of hydrogen partial pressure and reduction time for maximizing carbon yield, the CNT average diameter did not have a significant change, while the CNT crystallinity showed opposite trends depending on the methane decomposition reaction time. Ultimately, it was confirmed that the Mo-Fe/MgO catalyst can change the properties of CNTs produced through control of reduction conditions.
Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we ...reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141
CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.
A low-cost 80×60 microbolometer CMOS (complementary metal-oxide-semiconductor) thermal imager is presented. The imager system integrated with a proposed 12-b biasing digital-to-analog converter (DAC) ...has 100 ms start-up time, which is 300× faster than commercial products, while ensuring comparable 100 mK noise-equivalent temperature difference. The low-noise biasing DAC adopts a current-mode divider-stacking structure and a bit-inversion technique, leading to mismatch-insensitive operation. The 12-b biasing DAC in a 0.18 μ m CMOS imager IC has a low noise of 1.89 μ V rms and INL (integral non-linearity)/DNL (differential non-linearity) of 0.14/0.09 LSB, respectively.
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