Exosomes originating from neural stem cells undergoing necroptosis participate in cellular communication by inducing TSC2 upregulation of recipient cells following spinal cord injury.

ABSTRACT: We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury. While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function, their precise function in spinal cord injury remains unclear. To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury, we conducted single-cell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury. Subsequently, we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes. The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes. Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs, 104 long non-coding RNAs, 720 circular RNAs, and 14 microRNAs compared with the control group. Construction of a competing endogenous RNA network identified the following hub genes: tuberous sclerosis 2 (Tsc2), solute carrier family 16 member 3 (Slc16a3), and forkhead box protein P1 (Foxpl). Notably, a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury. TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone. Furthermore, in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells. Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways. In addition, Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways. Collectively, these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.

Effects of ibuprofen in the ZDF rat model of type 2 diabetes.

We aimed to investigate the therapeutic potential of ibuprofen against type 2 diabetes (T2D) using obese Zucker diabetic fatty (ZDF) rats as type 2 diabetes model. ZDF rats were hyperglycemic, dyslipidemic and expressed proinflammatory markers in contrast to lean controls, thus reflecting the relationship between obesity and chronic inflammation promoting T2D. Chronic treatment with ibuprofen (2-(4-Isobutylphenyl)propanoic acid) was used to study the impact on pathological T2D conditions as compared to metformin (1,1-dimethylbiguanide) treated ZDF as well as lean controls. Ibuprofen decreased A1c but induced a high insulin release with improved glucose tolerance only after early time points (i.g., 15 and 30 min) resulting in a non-significant decline of AUC values and translating into a high HOMA-IR. In addition, ibuprofen significantly lowered cholesterol, free fatty acids and HDL-C. Some of these effects by ibuprofen might be based on its anti-inflammatory effects through inhibition of cytokine/chemokine signaling (i.g., COX-2, ICAM-1 and TNF-α) as measured in whole blood and epididymal adipose tissue by TaqMan and/or upregulation of anti-inflammatory cytokines (i.g., IL-4 and IL-13) by ELISA analysis in blood. In conclusion, our ZDF animal study showed positive effects of ibuprofen against diabetic complications such as inflammation and dyslipidemia but also demonstrated the risk of causing insulin resistance.

Nutraceutical Potential of Djulis (Chenopodium formosanum) Hull: Phytochemicals, Antioxidant Activity, and Liver Protection.

Djulis (Chenopodium formosanum), a traditional Taiwanese crop enriched with phenolic compounds and betalain pigments, is associated with various health benefits, including antioxidant and hepatoprotective effects. This study analysed the phytochemical content and antioxidant capacity of extracts from both the hull and kernel of Djulis. The hull extract, which contained higher levels of flavonoids and exhibited superior antioxidant activity compared to the kernel extract, was selected for further in vivo studies. These experiments showed that oral administration of the Djulis hull crude extract significantly mitigated lipopolysaccharide (LPS)-induced acute liver injury (ALI) in mice by increasing the activity of the antioxidant enzyme glutathione peroxidase (GPx), reducing plasma levels of pro-inflammatory cytokine interferon gamma (IFN-γ), and enhancing liver levels of the anti-inflammatory cytokine interleukin-4 (IL-4). Additionally, the extract demonstrated potential in inhibiting the TLR4/NF-κB pathway, a critical signalling pathway in inflammation and apoptosis, offering insights into its protective mechanisms. These findings underscore Djulis hull's potential as a functional food ingredient for ALI prevention and propose a valuable application for agricultural by-products.

Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice.

SCOPE: Norisoboldine (NOR) is a major isoquinoline alkaloid component in the traditional Chinese herbal plant Lindera aggregata (Sims) Kosterm, with previously reported anti-osteoclast differentiation and antiarthritis properties. However, the roles of NOR on osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoporosis in vivo have never been well established. METHODS AND RESULTS: This study investigates the ability of NOR to improve bone formation in vitro and in vivo. Osteoblasts and BMSCs are used to study the effect of NOR on osteogenic and adipogenic differentiation. It finds that NOR promotes osteogenic differentiation of osteoblasts and BMSCs, while inhibiting adipogenic differentiation of BMSCs by reducing the relative expression of peroxisome proliferator-activated receptor Î³ (Ppar-γ) and adiponectin, C1Q and collagen domain containing (Adipoq). Mechanistic studies show that NOR increases osteoblast differentiation through the mechanistic target of rapamycin kinase (mTOR)/ribosomal protein S6 kinase; polypeptide 1 (S6K1) pathway, and treatment with an mTOR inhibitor rapamycin blocked the NOR-induced increase in mineral accumulation. Finally, the study evaluates the therapeutic potential of NOR in a mouse model of ovariectomy (OVX)-induced bone loss. NOR prevents bone loss in both trabecular and cortical bone by increasing osteoblast number and phospho-S6K1 (p-S6K1) expression in osteoblasts. CONCLUSION: NOR effects in enhancing osteoblast-induced bone formation via S6K1 pathway, suggesting the potential of NOR in osteoporosis treatment by increasing bone formation.

Formation of Volatile Pyrazinones in Amadori Rearrangement Products and Maillard Reaction Systems and the Major Formation Pathways.

Amadori rearrangement products (ARPs) are gaining more attention for their potential usage in the food flavor industry. Peptide-ARPs have been studied, but pyrazinones that were theoretically found in the Maillard reaction (MR) have not been reported to be formed from small peptide-ARPs. This study found four pyrazinones: 1-methyl-, 1,5-dimethyl-, 1,6-dimethyl-, and 1,5,6-trimethyl-2(1H)-pyrazinones in both MR and ARP systems. It was the first time 1-methyl-2(1H)-pyrazinone was reported, along with 1,5-dimethyl- and 1,5,6-trimethyl-2(1H)-pyrazinones being purified and analyzed by nuclear magnetic resonance for the first time. The primary formation routes of the pyrazinones were also proven as the reaction between diglycine and α-dicarbonyls, including glyoxal, methylglyoxal, and diacetyl. The pyrazinones, especially 1,5-dimethyl-2(1H)-pyrazinone, have strong fluorescence intensity, which may be the reason for the increase of fluorescence intensity in MR besides α-dicarbonyls. Cytotoxicity analysis showed that both Gly-/Digly-/Trigly-ARP and the three pyrazinones [1-methyl-, 1,5-dimethyl-, and 1,5,6-trimethyl-2(1H)-pyrazinones] showed no prominent cytotoxicity in the HepG2 cell line below 100 µg/mL, further suggesting that ARPs or pyrazinones could be used as flavor additives in the future. Further research should be conducted to investigate pyrazinones in various systems, especially the peptide-ARPs, which are ubiquitous in real food systems.

Anti-Inflammatory Effects of Anthocyanin-Enriched Black Soybean Seed Coat (BSSC) Crude Extract on LPS-Induced Acute Liver Injury in Mice.

Soybeans rank among the top five globally produced crops. Black soybeans contain anthocyanins in their seed coat, offering strong antioxidant and anti-inflammatory benefits. This study explores the protective effects of black soybean seed coat (BSSC) against acute liver injury (ALI) in mice. Mice pretreated with BSSC crude extract showed reduced liver damage, inflammation, and apoptosis. High doses (300 mg/kg) of the extract decreased levels of proinflammatory cytokines (IL-6, IFN-γ) and increased levels of anti-inflammatory ones (IL-4, IL-10), alongside mitigating liver pathological damage. Additionally, it influenced the Nrf2/HO-1 pathway and reduced levels of apoptosis-related proteins. In vitro, the compounds delphinidin-3-O-glucoside (D3G) and cyanidin-3-O-glucoside (C3G) in BSSC were found to modulate cytokine levels, suggesting their role in ALI protection. The study concludes that BSSC extract, particularly due to D3G and C3G, effectively protects against LPS-induced ALI in mice by inhibiting inflammation, oxidative stress, and apoptosis.

A fault diagnosis method for wireless sensor network nodes based on a belief rule base with adaptive attribute weights.

Due to the harsh operating environment and ultralong operating hours of wireless sensor networks (WSNs), node failures are inevitable. Ensuring the reliability of the data collected by the WSN necessitates the utmost importance of diagnosing faults in nodes within the WSN. Typically, the initial step in the fault diagnosis of WSN nodes involves extracting numerical features from neighboring nodes. A solitary data feature is often assigned a high weight, resulting in the failure to effectively distinguish between all types of faults. Therefore, this study introduces an enhanced variant of the traditional belief rule base (BRB), called the belief rule base with adaptive attribute weights (BRB-AAW). First, the data features are extracted as input attributes for the model. Second, a fault diagnosis model for WSN nodes, incorporating BRB-AAW, is established by integrating parameters initialized by expert knowledge with the extracted data features. Third, to optimize the model's initial parameters, the projection covariance matrix adaptive evolution strategy (P-CMA-ES) algorithm is employed. Finally, a comprehensive case study is designed to verify the accuracy and effectiveness of the proposed method. The results of the case study indicate that compared with the traditional BRB method, the accuracy of the proposed model in WSN node fault diagnosis is significantly improved.

Study on the Influence of Label Image Accuracy on the Performance of Concrete Crack Segmentation Network Models.

A high-quality dataset is a basic requirement to ensure the training quality and prediction accuracy of a deep learning network model (DLNM). To explore the influence of label image accuracy on the performance of a concrete crack segmentation network model in a semantic segmentation dataset, this study uses three labelling strategies, namely pixel-level fine labelling, outer contour widening labelling and topological structure widening labelling, respectively, to generate crack label images and construct three sets of crack semantic segmentation datasets with different accuracy. Four semantic segmentation network models (SSNMs), U-Net, High-Resolution Net (HRNet)V2, Pyramid Scene Parsing Network (PSPNet) and DeepLabV3+, were used for learning and training. The results show that the datasets constructed from the crack label images with pix-el-level fine labelling are more conducive to improving the accuracy of the network model for crack image segmentation. The U-Net had the best performance among the four SSNMs. The Mean Intersection over Union (MIoU), Mean Pixel Accuracy (MPA) and Accuracy reached 85.47%, 90.86% and 98.66%, respectively. The average difference between the quantized width of the crack image segmentation obtained by U-Net and the real crack width was 0.734 pixels, the maximum difference was 1.997 pixels, and the minimum difference was 0.141 pixels. Therefore, to improve the segmentation accuracy of crack images, the pixel-level fine labelling strategy and U-Net are the best choices.

Hypoglycemic effects and associated mechanisms of resveratrol and related stilbenes in diet.

Hyperglycemia has become a global health problem due to changes in diet and lifestyle. Most importantly, persistent hyperglycemia can eventually develop into type II diabetes. While the usage of current drugs is limited by their side effects, stilbenes derived from fruits and herbal/dietary plants are considered as important phytochemicals with potential hypoglycemic properties. Herein, the most common stilbenoids in consumed foods, i.e. resveratrol, pterostilbene, piceatannol, oxyresveratrol, and 2,3,5,4'-tetrahydroxystilbene-2-O-ß-glucopyranoside (THSG), are reviewed in this paper. These stilbenes are found to regulate glucose homeostasis via (a) modulation of feeding behaviour and nutrition absorption; (b) restoration of insulin signalling by enhancing insulin production/insulin sensitivity; (c) improvement of gut permeability, gut microbial profile and resulting metabolomes; and (d) amelioration of circadian rhythm disruption. In this review, we have summarized the underlying mechanisms for the hypoglycemic effects of the five most common dietary stilbenoids listed above, providing a comprehensive framework for future study and applications.

Extracellular vesicles released by transforming growth factor-beta 1-preconditional mesenchymal stem cells promote recovery in mice with spinal cord injury.

Spinal cord injury (SCI) causes neuroinflammation, neuronal death, and severe axonal connections. Alleviating neuroinflammation, protecting residual cells and promoting neuronal regeneration via endogenous neural stem cells (eNSCs) represent potential strategies for SCI treatment. Extracellular vesicles (EVs) released by mesenchymal stem cells have emerged as pathological mediators and alternatives to cell-based therapies following SCI. In the present study, EVs isolated from untreated (control, C-EVs) and TGF-ß1-treated (T-EVs) mesenchymal stem cells were injected into SCI mice to compare the therapeutic effects and explore the underlying mechanisms. Our study demonstrated for the first time that the application of T-EVs markedly enhanced the proliferation and antiapoptotic ability of NSCs in vitro. The infusion of T-EVs into SCI mice increased the shift from the M1 to M2 polarization of reactive microglia, alleviated neuroinflammation, and enhanced the neuroprotection of residual cells during the acute phase. Moreover, T-EVs increased the number of eNSCs around the epicenter. Consequently, T-EVs further promoted neurite outgrowth, increased axonal regrowth and remyelination, and facilitated locomotor recovery in the chronic stage. Furthermore, the use of T-EVs in Rictor-/- SCI mice (conditional knockout of Rictor in NSCs) showed that T-EVs failed to increase the activation of eNSCs and improve neurogenesis sufficiently, which suggested that T-EVs might induce the activation of eNSCs by targeting the mTORC2/Rictor pathway. Taken together, our findings indicate the prominent role of T-EVs in the treatment of SCI, and the therapeutic efficacy of T-EVs for SCI treatment might be optimized by enhancing the activation of eNSCs via the mTORC2/Rictor signaling pathway.

Gallic acid ameliorates colitis by trapping deleterious metabolite ammonia and improving gut microbiota dysbiosis.

Gut microbiota dysbiosis is causally related to inflammatory bowel disease (IBD), and increased levels of the gut metabolite ammonia have been proposed to contribute to IBD development. In this study, we aimed to clarify the anti-colitis mechanism of gallic acid (GA) based on its ability to trap the deleterious metabolite ammonia and improve gut microbiota. Aminated product was detected in the fecal samples of mice after oral gavage of gallic acid (GA) and identified as 4-amino-substituted gallic acid (4-NH2-GA), thus confirming the ability of GA to trap ammonia in vivo. Then, we compared the beneficial effects of GA and 4-NH2-GA on dextran sulfate sodium (DSS)-induced colitis mouse and found that both compounds managed to alleviate colitis phenotypes, indicating ammonia trapping had no adverse effect on the original anti-colitis activity of GA. In addition, both GA and 4-NH2-GA improved the gut microbiota dysbiosis induced by DSS, and fecal microbiota transplantation was subsequently performed, which further revealed that the gut microbiota mediated the anti-colitis activity of both GA and 4-NH2-GA. In summary, this study clarified that GA alleviated colitis by targeting both the symptoms and root causes: it directly reduced the deleterious metabolite ammonia by forming aminated metabolites without compromising the original anti-colitis activity, and it also improved gut microbiota dysbiosis, which in turn contributed to the alleviation of colitis. Since the GA structure is presented in various polyphenols as a common building block, the novel anti-colitis mechanism obtained from GA may also apply to other complex polyphenols.IMPORTANCEThe dysbiosis of the gut microbiota and its metabolism directly cause the emergence of IBD. In this study, we aimed to clarify the anti-colitis mechanism of GA in sight of gut microbiota and its metabolite ammonia. We discovered that GA directly captured and reduced the harmful metabolite ammonia in vivo to produce the aminated metabolite 4-NH2-GA, while the amination of GA had no adverse effect on its initial anti-colitis activity. In addition, both GA and its aminated metabolite improved the gut microbiota in colitis mice, and the modified gut microbiota, in turn, helped to relieve colitis. Since the GA structure is presented in diverse polyphenols as a common building block, the novel anti-colitis mechanism targeting the symptoms and root causes might also apply to other complex polyphenols.

Incidence and influencing factors of post-stroke cognitive impairment in convalescent young patients with first-ever stroke.

OBJECTIVE: To investigate the occurrence of post-stroke cognitive impairment (PSCI) and its influencing factors in convalescent young patients with first-ever stroke. METHODS: A total of 300 first-ever young stroke patients (age ≤45 years) were collected. The Mini-Mental State Examination (MMSE) was used to assess the cognitive status. The sociodemographic data, clinical symptoms, social environment, and behavior-related information were collected and analyzed. RESULTS: The incidence of PSCI in young stroke patients was 62.33 %. Through univariate analysis, there were statistical differences in different levels of education, smoking status and hypertension (P < 0.05). With subsequently multivariate logistic regression analysis, it was found that junior high school (OR=8.58,95 %CI:2.25∼32.70) and high school (OR=10.50,95 %CI:2.69∼41.00) education levels, lesion volume >3.00 cm3 (OR=8.03,95 %CI:2.28∼28.36), stroke in the frontal-parietal-temporal region (OR=7.26,95 %CI:1.58∼33.40) and the basal ganglia area (OR=6.13,95 %CI:1.24∼30.43), high NIHSS score (OR=1.17,95 %CI: 1.06∼1.29), and high diastolic blood pressure variability coefficient (OR=1.43,95 %CI: 1.02∼2.01) were risk factors for PSCI. Meanwhile, 24≤BMI<28 (OR=0.06,95 %CI:0.02∼0.23) and BMI<24 (OR=0.18,95 %CI:0.06∼0.53), hospitalization cost >20,000/month (OR=0.22,95 %CI:0.09∼0.56), and stroke onset in spring and summer (OR=0.37,95 %CI:0.14∼0.96) were protective factors. CONCLUSION: The incidence of PSCI is relatively high in young stroke patients. Junior high and high school education, stroke lesions >3.00cm3, strokes in the frontal-parietal-temporal and basal ganglia regions, high NIHSS scores, and high DBPV are risk factors for PSCI in young stroke patients. Meanwhile, BMI<28, treatment cost >20,000/month, and stroke onset in spring and summer are protective factors for PSCI in young stroke patients.

The effect of blood flow restriction exercise on N-lactoylphenylalanine and appetite regulation in obese adults: a cross-design study.

Background: N-lactoylphenylalanine (Lac-Phe) is a new form of "exerkines" closely related to lactate (La), which may be able to inhibit appetite. Blood flow restriction (BFR) can lead to local tissue hypoxia and increase lactate accumulation. Therefore, this study investigated the effects of combining Moderate-intensity Continuous Exercise (MICE) with BFR on Lac-Phe and appetite regulation in obese adults. Methods: This study employed the cross-design study and recruited 14 obese adults aged 18-24 years. The participants were randomly divided into three groups and performed several tests with specific experimental conditions: (1) M group (MICE without BFR, 60%VO2max, 200 kJ); (2) B group (MICE with BFR, 60%VO2max, 200 kJ); and (3) C group (control session without exercise). Participants were given a standardized meal 60 min before exercise and a ad libitum 60 min after exercise. In addition, blood and Visual Analogue Scale (VAS) were collected before, immediately after, and 1 hour after performing the exercise. Results: No significant difference in each index was detected before exercise. After exercise, the primary differential metabolites detected in the M and B groups were xanthine, La, succinate, Lac-Phe, citrate, urocanic acid, and myristic acid. Apart from that, the major enrichment pathways include the citrate cycle, alanine, aspartate, and glutamate metabolism. The enhanced Lac-Phe and La level in the B group was higher than M and C groups. Hunger of the B group immediately after exercise substantially differed from M group. The total ghrelin, glucagon-like peptide-1 and hunger in the B group 1 hour after exercise differed substantially from M group. The results of calorie intake showed no significant difference among the indexes in each group. Conclusions: In conclusion, this cross-design study demonstrated that the combined MICE and BFR exercise reduced the appetite of obese adults by promoting the secretion of Lac-Phe and ghrelin. However, the exercise did not considerably affect the subsequent ad libitum intake.

Integrating genomic and multiomic data for Angelica sinensis provides insights into the evolution and biosynthesis of pharmaceutically bioactive compounds.

Angelica sinensis roots (Angelica roots) are rich in many bioactive compounds, including phthalides, coumarins, lignans, and terpenoids. However, the molecular bases for their biosynthesis are still poorly understood. Here, an improved chromosome-scale genome for A. sinensis var. Qinggui1 is reported, with a size of 2.16 Gb, contig N50 of 4.96 Mb and scaffold N50 of 198.27 Mb, covering 99.8% of the estimated genome. Additionally, by integrating genome sequencing, metabolomic profiling, and transcriptome analysis of normally growing and early-flowering Angelica roots that exhibit dramatically different metabolite profiles, the pathways and critical metabolic genes for the biosynthesis of these major bioactive components in Angelica roots have been deciphered. Multiomic analyses have also revealed the evolution and regulation of key metabolic genes for the biosynthesis of pharmaceutically bioactive components; in particular, TPSs for terpenoid volatiles, ACCs for malonyl CoA, PKSs for phthalide, and PTs for coumarin biosynthesis were expanded in the A. sinensis genome. These findings provide new insights into the biosynthesis of pharmaceutically important compounds in Angelica roots for exploration of synthetic biology and genetic improvement of herbal quality.

CTSF: An Intrusion Detection Framework for Industrial Internet Based on Enhanced Feature Extraction and Decision Optimization Approach.

The traditional Transformer model primarily employs a self-attention mechanism to capture global feature relationships, potentially overlooking local relationships within sequences and thus affecting the modeling capability of local features. For Support Vector Machine (SVM), it often requires the joint use of feature selection algorithms or model optimization methods to achieve maximum classification accuracy. Addressing the issues in both models, this paper introduces a novel network framework, CTSF, specifically designed for Industrial Internet intrusion detection. CTSF effectively addresses the limitations of traditional Transformers in extracting local features while compensating for the weaknesses of SVM. The framework comprises a pre-training component and a decision-making component. The pre-training section consists of both CNN and an enhanced Transformer, designed to capture both local and global features from input data while reducing data feature dimensions. The improved Transformer simultaneously decreases certain training parameters within CTSF, making it more suitable for the Industrial Internet environment. The classification section is composed of SVM, which receives initial classification data from the pre-training phase and determines the optimal decision boundary. The proposed framework is evaluated on an imbalanced subset of the X-IIOTID dataset, which represent Industrial Internet data. Experimental results demonstrate that with SVM using both "linear" and "rbf" kernel functions, CTSF achieves an overall accuracy of 0.98875 and effectively discriminates minor classes, showcasing the superiority of this framework.

Corneal metabolic biomarkers for moderate and high myopia in human.

This study aimed to identify the corneal metabolic biomarkers for moderate and high myopia in human. We enrolled 221 eyes from 221 subjects with myopia to perform the femtosecond laser small incision lenticule extraction (SMILE) surgery. Among these, 71 eyes of 71 subjects were enrolled in the low myopic group, 75 eyes of 75 subjects in the moderate myopic group and 75 eyes of 75 subjects in the high myopic group. The untargeted metabolomics analysis was performed to analyze the corneal tissues extracted during the SMILE surgery using an ultra-high-performance liquid chromatography (UHPLC) coupled to a quadrupole time-of-flight (Q-TOF) mass spectrometry (MS). The one-way analysis of variance (ANOVA) was used to identify the different metabolites among the three myopic groups, the orthogonal partial least-squares discriminant analysis (OPLS-DA) model was used to reveal the different metabolites between moderate myopia and low myopia, and between high myopia and low myopia. The Venn gram was used to find the overlapped metabolites of the three datasets of the different metabolites. The stepwise multiple linear regression analysis was used to determine the metabolic molecules associated with manifest refractive spherical equivalents (MRSE). The Receiver Operating Characteristics (ROC) analysis was performed to reveal the corneal biomarkers for moderate and high myopia. The hub biomarker was further selected by the networks among different metabolites created by the Cytoscape software. A total of 1594 metabolites were identified in myopic corneas. 321 metabolites were different among the three myopic groups, 106 metabolites were different between high myopic corneas and low myopic corneas, 104 metabolites were different between moderate myopic corneas and low myopic corneas, and 30 metabolic molecules overlapped among the three datasets. The multivariate linear regression analysis revealed the myopic degree was significantly influenced by the corneal levels of azelaic acid, arginine-proline (Arg-Pro), 1-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, and hypoxanthine. The ROC curve analysis showed that azelaic acid, Arg-Pro and hypoxanthine were effective in discriminating low myopia from moderate to high myopia with the area under the curve (AUC) values as 0.982, 0.991 and 0.982 for azelaic acid, Arg-Pro and hypoxanthine respectively. The network analysis suggested that Arg-Pro had the maximum connections among these three biomarkers. Thus, this study identified azelaic acid, Arg-Pro and hypoxanthine as corneal biomarkers to discriminate low myopia from moderate to high myopia, with Arg-Pro serving as the hub biomarker for moderate and high myopia.

Mesoporous silica-based nanocarriers with dual response to pH and ROS for enhanced anti-inflammation therapy of 5-demethylnobiletin against psoriasis-like lesions.

Psoriasis is an inflammatory skin disease accompanied with chronic papulosquamous lesions and multiple comorbidities that considerably affect patients' quality of life. In order to develop an enhanced therapeutic strategy for psoriasis, 5-demethylnobiletin (5-DN), a kind of polymethoxyflavones (PMFs) with high anti-inflammatory activity, was delivered in vitro and in vivo by the nanocarrier of mesoporous silica nanoparticles (MSNs) both in the human keratinocytes HaCaT cell line and the mouse model with psoriasis-like lesions. The drug-loaded nanocarrier system (MSNs@5-DN) significantly improved the biocompatibility and bioavailability of 5-DN. Investigations at cell biological, histopathological, and molecular levels revealed the pharmacological mechanism of the drug delivery system, including the inhibition of inflammatory responses by downregulating the proinflammatory cytokine levels of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). The upregulation of anti­inflammatory cytokine of transforming growth factor-ß1 (TGF-ß1) and microRNA-17-5p, a critical regulator of the PTEN/AKT pathway, was also observed. The psoriasis-like lesions were markedly ameliorated in the mouse models treated with MSNs@5-DN. The designed drug-loading system shows an enhanced therapeutic outcome for psoriasis-like lesion compared with free 5-DN. This study revealed the synergistic effect of functionalized MSNs loaded with PMFs on the clinical treatment of human psoriasis.

AMPK Mediates Early Activation of the Unfolded Protein Response through a Positive Feedback Loop in Palmitate-Treated Muscle Cells.

BACKGROUND: Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and metabolic signaling pathways are interdependent. The AMP-activated protein kinase (AMPK) signal pathway controls the energy balance of eukaryotes. The aim of this study was therefore to investigate the possible interaction between AMPK signaling and UPR in muscle cells exposed to saturated fatty acids, as well as the potential mechanism. METHODS: The saturated fatty acid palmitate was used to induce UPR in C2C12 myotubes. Compound C or knockdown of AMPKα with short hairpin RNA (shRNA) were used to inhibit the AMPK signaling pathway in palmitate-treated muscle cells. AMPK signaling in myotubes was activated using 5-amino-1-ß-D-ribofuranosylimidazole-4-carboxamide (AICAR) or ex229. C2C12 myotubes were pre-treated with taurourdodeoxycholic acid (TUDCA) to inhibit UPR before adding palmitate. Real-time PCR and Western blotting were performed to evaluate the expression of UPR markers and activation of AMPK. RESULTS: Palmitate treatment induced UPR in C2C12 myotubes while activating AMPK signaling. Inhibition of the AMPK pathway with compound C or AMPK shRNA reduced palmitate-induced activation of UPR, while inhibition of UPR with TUDCA reduced palmitate-induced AMPK activation. This indicates a positive feedback loop between UPR and AMPK. Furthermore, activation of the AMPK pathway with AICAR or ex229 caused a dose-dependent upregulation of UPR markers, including activating transcription factor 4 (ATF4), binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible 34 (GADD34) protein. CONCLUSIONS: These results provide the first evidence that AMPK signaling is involved in the early activation of UPR caused by saturated fatty acids in skeletal muscle. Furthermore, they indicate that physiological or pharmacological activation of the AMPK pathway (e.g., by exercise or phenformin, respectively) can promote muscle health and function, thereby improving the quality of life in individuals with metabolic disorders due to a high-fat diet or obesity.