Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

Introduction: Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. Methods: CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Results: Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. Discussion: The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

cNPAS2 induced ß cell dysfunction by regulating KANK1 expression in type 2 diabetes.

BACKGROUND: Diabetes mellitus type 2 (T2DM) is formed by defective insulin secretion with the addition of peripheral tissue resistance of insulin action. It has been affecting over 400 million people all over the world. AIM: To explore the pathogenesis of T2DM and to develop and implement new prevention and treatment strategies for T2DM. METHODS: Receiver operating characteristic (ROC) curve analysis was used to conduct diagnostic markers. The expression level of genes was determined by reverse transcription-PCR as well as Western blot. Cell proliferation assays were performed by cell counting kit-8 (CCK-8) tests. At last, T2DM mice underwent Roux-en-Y gastric bypass surgery. RESULTS: We found that NPAS2 was significantly up-regulated in islet ß cell apoptosis of T2DM. The ROC curve revealed that NPAS2 was capable of accurately diagnosing T2DM. NPAS2 overexpression did increase the level of KANK1. In addition, the CCK-8 test revealed knocking down NPAS2 and KANK1 increased the proliferation of MIN6 cells. At last, we found that gastric bypass may treat type 2 diabetes by down-regulating NPAS2 and KANK1. CONCLUSION: This study demonstrated that NPAS2 induced ß cell dysfunction by regulating KANK1 expression in type 2 diabetes, and it may be an underlying therapy target of T2DM.

Lysophospholipid acyltransferase-mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation.

Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi-omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up-regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1-mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia-related diseases.

Compact Bandwidth-Enhanced 180-Degree Phase Shifter Using Edge-Coupled Multi-Microstrip and Artificial Transmission Line.

Compactness has obtained sufficient importance in wideband phase shifter design considerations, as it is directly related to fabrication cost. In this paper, a novel structure was presented to create compact broadband 180-degree phase shifter, which has the advantages of enhanced bandwidth and significantly reduced chip area. The proposed configuration consists of edge-coupled multi-microstrip lines (ECMML) and an artificial transmission line (ATL) with dual-shorted inductors, both of which have the periodic shunt load of capacitors. The ECMML can provide a high coupling coefficient, leading to an increase in the bandwidth, while the introduced capacitors can greatly reduce the line length (35.8% of the conventional method). To verify the relevant mechanisms, a wideband switched network with compact dimensions of 0.67 × 0.46 mm2 was designed via 0.15-micrometer GaAs pHEMT technology. Combined with the measured switch transistor, it was shown that the proposed phase shifter exhibits an insertion loss of less than 2 dB, a return loss of greater than 12 dB, a maximum phase error of less than 0.6° and a channel amplitude difference of less than 0.1 dB in the range of 10 to 20 GHz.

A Ku-Band Broadband Stacked FET Power Amplifier Using 0.15 µm GaAs pHEMT.

To meet the application requirements of broadband radar systems for broadband power amplifiers, a Ku-band broadband power amplifier (PA) microwave monolithic integrated circuit (MMIC) based on a 0.15 µm gallium arsenide (GaAs) high-electron-mobility transistor (HEMT) technology is proposed in this paper. In this design, the advantages of the stacked FET structure in the broadband PA design are illustrated by theoretical derivation. The proposed PA uses a two-stage amplifier structure and a two-way power synthesis structure to achieve high-power gain and high-power design, respectively. The fabricated power amplifier was tested under continuous wave conditions, and the test results showed a peak power of 30.8 dBm at 16 GHz. At 15 to 17.5 GHz, the output power was above 30 dBm with a PAE of more than 32%. The fractional bandwidth of the 3 dB output power was 30%. The chip area was 3.3 × 1.2 mm2 and included input and output test pads.

Prognostic capacity of the systemic inflammation response index for functional outcome in patients with aneurysmal subarachnoid hemorrhage.

Objective: We aimed to investigate the relationship between systemic inflammatory response index (SIRI) and functional outcome after aneurysmal subarachnoid hemorrhage (aSAH). Methods: A retrospective cohort study was performed involving all consecutive aSAH patients admitted to our institution. The modified Rankin Scale (mRS) score was performed to determine the functional outcomes of all patients at 3 months after aSAH. Results were categorized as favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Univariate and multivariate logistic regressive analyses were utilized to identify the prognostic significance of SIRI. To minimize the effects of confounding factors, patients were stratified according to the optimal cut-off value of SIRI with propensity score matching (PSM). Further subgroup analysis was conducted to verify the consistency of our findings and Pearson's correlation analysis was used to assess the relationship between SIRI and the severity of aSAH. Results: In this study, 350 patients were enrolled and 126 (36.0%) of them suffered unfavorable outcomes. The SIRI of 5.36 × 109/L was identified as the optimal cut-off value. Two score-matched cohorts (n = 100 in each group) obtained from PSM with low SIRI and high SIRI were used for analysis. A significantly higher unfavorable functional outcome rate was observed in patients with high SIRI before and after PSM (p < 0.001 and 0.017, respectively). Multivariate logistic regression analysis demonstrated that SIRI value ≥ 5.36 × 109/L was an independent risk factor for poor outcomes (OR 3.05 95% CI 1.37-6.78, p = 0.006) after adjusting for possible confounders. A identical result was discovered in the PSM cohort. In ROC analysis, the area under the curve (AUC) of SIRI was 0.774 which shown a better predictive value than other inflammatory markers observed in previous similar studies. Pearson's correlation analysis proved the positive association between SIRI and aSAH severity. Conclusions: Elevated SIRI at admission is associated with worse clinical status and poorer functional outcomes among patients with aSAH. SIRI is a useful inflammatory marker with prognostic value for functional outcomes after aSAH.

Dietary fiber extraction from citrus peel pomace: Yield optimization and evaluation of its functionality, rheological behavior, and microstructure properties.

Citrus fruits were widely used in processing and production, generating a large amount of peel pomace and a low utilization rate, resulting in substantial economic losses and environmental risks. It was important to extract compounds from citrus peel pomaces and find suitable preparation methods to improve their yield and physicochemical properties. Grapefruit peel pomace (GP) and navel orange peel pomace (OP) were used as raw materials in this study to prepare green and edible soluble dietary fiber (SDF) and insoluble dietary fiber (IDF). Analysis was done on the effects of solid-liquid ratio, cellulase hydrolysis time, cellulase dosage, and ultrasonic time on dietary fiber (DF) yield. To obtain the best DF preparation conditions, we used range analysis, variance analysis, and orthogonal experimental design. We also analyzed the structural, physicochemical, and rheological characteristics of SDF and IDF. According to the study's findings, SDF and IDF showed a loose and expansive structure with reduced particle size, higher specific surface area, and noticeably better physical and chemical properties after treating GP and OP with ultrasound-assisted composite enzyme method. Both SDF solution and IDF suspension were discovered through rheological analysis to be non-Newtonian pseudoplastic fluids, which was advantageous for expanding their applications in the field of food packaging. In conclusion, DF prepared using the ultrasound-assisted composite enzyme method was an excellent source of edible packaging materials, offering a benchmark for the recycling of other citrus peel wastes and ultimately paving the way for new methods of recycling citrus waste.

Theoretical Study on the Swelling Mechanism and Structural Stability of Ni3Al-LDH Based on Molecular Dynamics.

layered double hydroxide (LDH) as a kind of 2D layer material has a swelling phenomenon. Because swelling significantly affects the adsorption, catalysis, energy storage, and other application properties of LDHs, it is essential to study the interlayer spacing, structural stability, and ion diffusion after swelling. In this paper, a periodic computational model of Ni3Al-LDH is constructed, and the supramolecular structure, swelling law, stability, and anion diffusion properties of Ni3Al-LDH are investigated by molecular dynamics theory calculations. The results show that the interlayer water molecules of Ni3Al-LDH present a regular layered arrangement, combining with the interlayer anions by hydrogen bonds. As the number of water molecules increases, the hydrogen bond between the anion and the basal layer gradually weakens and disappears when the number of water molecules exceeds 32. The hydrogen bond between the anion and the water molecule gradually increases, reaching an extreme value when the number of water molecules is 16. The interlayer spacing of Ni3Al-LDH is not linear with the number of water molecules. The interlayer spacing increases slowly when the number of water molecules is more than 24. The maximum layer spacing is stable at around 19 Å. The interlayer spacing, binding energy, and hydration energy show an upper limit for swelling: the number of water molecules is 32. When the number of interlayer water molecules is 16, the water molecules' layer structure and LDH interlayer spacing are suitable for anions to obtain the maximum diffusion rate, 10.97 × 10-8 cm2·s-1.

Zinc finger protein 501 maintains glioblastoma cell growth through enhancing Frizzled-6 expression.

Understanding the regulatory mechanisms of glioblastoma growth is crucial for developing novel therapies. In this study, the expression and function of zinc finger protein 501 (ZNF501) in human glioblastoma cells were characterized. ZNF501 was abundantly expressed in human glioblastoma cell lines U251, U118, U87, and U138. ZNF501 ablation in these cell lines caused inhibition of proliferation, sphere formation, and the expression of SOX2 and OCT4. Besides, ZNF501 ablation increased the sensitivity of these cell lines to Temozolomide but did not influence cell migration. Orthotopic implantation of U251 cells and U118 cells indicated that ZNF501 ablation suppressed glioblastoma cell proliferation and tumor formation in vivo. ZNF501 ablation induced down-regulation of Frizzled-6 (FZD6), a component of the Wnt signaling. Lentivirus-mediated FZD6 overexpression restored the proliferation, sphere formation, drug sensitivity, and SOX2 and OCT4 expression in these cell lines. ZNF501 ablation also incurred down-regulation of JNK phosphorylation which is an indicator of the non-canonical Wnt signaling, but did not change the expression of active ß-catenin which is the hallmark of the canonical Wnt signaling. Inhibition of the non-canonical Wnt signaling abrogated the effects of ZNF501 and FZD6. Therefore, for the first time, we showed that ZNF501 is essential for the growth and stemness of glioblastoma cells possibly by maintaining FZD6 expression and the non-canonical Wnt signaling.

First-Principles Study on Interlayer Spacing and Structure Stability of NiAl-Layered Double Hydroxides.

Interlayer spacing and structure stability of layered double hydroxides (LDHs) on their application performance in adsorption, ion exchange, catalysis, carrier, and energy storage is important. The effect of different interlayer anions on the interlayer spacing and structure stability of LDHs has been less studied, but it is of great significance. Therefore, based on density functional theory (DFT), the computational model with 10 kinds of anions intercalated Ni3Al-A-LDHs (A = Cl-, Br-, I-, OH-, NO3 -, CO3 2-, SO4 2-, HCOO-, C6H5SO3 -, C12H25SO3 -) and four Ni R Al-Cl-LDH models with different Ni2+/Al3+ ratios (R = 2, 3, 5, 8) were constructed to calculate and analyze interlayer spacing, structural stability, and their influence factors. It was found that the interlayer spacing order of Ni3Al-A-LDHs intercalated with different anions is OH- < CO3 2- < Cl- < Br- < I- < HCOO- < SO4 2- < NO3 - < C6H5SO3 - < C12H25SO3 -. The hydrogen bond network between the base layer and the interlayer anions affects the arrangement structure of the interlayer anions, which affects the interlayer spacing. For interlayer monatomic anions Cl-, Br-, and I- and the anion of comparable size in each direction SO4 2-, the interlayer spacing is positively correlated with the interlayer anion diameter. The larger difference between the long-axis and short-axis dimensions of the polyatomic anions results in the long axis of the anion being perpendicular to the basal layer, increasing interlayer spacing. The long-chain anion C12H25SO3 - intercalation system exhibits the largest layer spacing of 24.262 Å. As R value increases from 2 to 8, the interlayer spacing of Ni R Al-Cl-LDHs gradually increases from 7.964 to 8.124 Å. The binding energy order between the interlayer anion and basal layer is CO3 2- > SO4 2- > OH- > Cl- > Br- > I- > HCOO- > NO3 - > C12H25SO3 - > C6H5SO3 -. The smaller the interlayer spacing, the higher the binding energy and the stronger the structural stability of LDHs. The factors affecting structural stability mainly include the bond length and bond angle of the hydrogen bond and the charge interaction between the basal layer and interlayer anion. In the CO3 2- intercalated system, the hydrogen bond length exhibits the shortest of 1.95 Å and the largest bond angle of 163.68°. The density of states and energy band analysis show that the higher the number of charges carried by the anion, the stronger its ability to provide electrons to the basal layer.

Double-layered osmotic pump controlled release tablets of actarit: In vitro and in vivo evaluation.

The aim of the study was to develop actarit double-layered osmotic pump tablets to overcome the weak points of actarit common tablets, such as short half-life and large plasma concentration fluctuations. Single factor experiment and orthogonal test were applied to optimize the formulation; the pharmacokinetic study was performed in beagle dogs adopting actarit common tablets as reference tablets. The optimal formulation was as follows: drug layer: 150 mg actarit, 240 mg PEO-N80, 50 mg NaCl; push layer: 140 mg PEO-WSR303, 20 mg NaCl; coating solution: 30 g cellulose acetate and 6 g PEG 4000 in 1000 ml 94% acetone solution, 60 mg coating weight gain. The pharmacokinetic study showed that T max was prolonged by the contrast of commercial common tablets with constant drug release rate, but the bioavailability was equivalent. And a good in vivo-in vitro correlation of the actarit osmotic pump tablets was also established. The designed actarit osmotic pump tablets can be applied for rheumatoid arthritis, proposing a promising replacement for the marked common products.