Exploring the anti-ischemic stroke potential of wogonoside: Insights from Nrf2/Sirt3 signaling pathway and UPLC-TripleTOF-MS/MS-based metabolomics.

Ischemic stroke, accounting for 80 % of all strokes, is a major cause of morbidity and mortality worldwide. However, effective and safe pharmacotherapy options for ischemic injury are limited. This study investigated the therapeutic effects of wogonoside, a compound derived from Radix Scutellariae, on ischemia/reperfusion (I/R) injury. The results showed that wogonoside treatment had significant therapeutic effects in rats with middle cerebral artery occlusion. It effectively reduced mortality rates, neurological deficits, cerebral infarct size, and brain water content. In an in vitro model using PC12 cells, wogonoside activated the Nrf2/Sirt3 signaling pathway. This activation contributed to the attenuation of oxidative damage and inflammation. Metabolomics analysis revealed increased levels of γ-aminobutyric acid (GABA) and glutathione in response to wogonoside treatment, suggesting their potential as therapeutic biomarkers for ischemic stroke. Additionally, wogonoside restored perturbed energy metabolism, including the tricarboxylic acid cycle. Wogonoside has the potential to ameliorate cerebral ischemic injury by targeting GABA-related amino acid metabolism, energy metabolism, and glutathione metabolism, maintaining redox homeostasis, and attenuating oxidative stress. These findings provide valuable insights into the protective mechanisms of wogonoside in cerebral I/R injury and highlight the promising therapeutic approach of wogonoside in the treatment of ischemic stroke.

Effect of structural support size and position on depressed tibial plateau fractures: A finite element analysis.

Objective: Structural support for depressed tibial plateau fractures is receiving increasing attention. Currently, there has been little biomechanical evaluation of structural support. This work aimed to investigate the effect of structural support size and position on fracture fixation stability. Methods: A split-depressed tibial plateau fracture model was created according to the fracture map. Cortical screws combined with structural filler were used for fracture fixation. The filler diameter was set to small, medium and large, and the filler position was set to the center and offset by 1, 2 and 3 mm to study the effect of position and size on stability. Results: The maximum stress on the implant in all scenarios occurs at the lower contact surface between the anterior screw and the filler. Increased support size resulted in increased mean maximum screw stress, depressed fragment axial displacement and separated fragment transverse displacement (screw stress: 266.6 ± 37.7 MPa vs. 266.7 ± 51.0 MPa vs. 273.8 ± 41.5 MPa; depressed displacement: 0.123 ± 0.036 mm vs. 0.133 ± 0.049 mm vs. 0.158 ± 0.050 mm; separated displacement: 0.402 ± 0.031 mm VS 0.412 ± 0.047 mm VS 0.437 ± 0.049 mm). The larger the offset of the support position was, the larger the peak screw stress and the larger the reduction loss of depressed and separated fragment reduction, regardless of the support size. The medium support combined with the central position presented the minimum of peak stress and reduction loss. Cortical bone was below 2 % and trabecular strain was below 10 % for all scenarios. Conclusion: Central placement of structural support provides superior stability for the treatment of depressed tibial plateau fractures compared to the eccentric placement. When a support is placed centrally, optimal stability is achieved when the diameter matches the diameter of the depressed region. Thus, the utilization of equal-diameter fillers to provide central support appears to be an ideal selection for depressed tibial plateau fractures.

Exploring the Constituents and Mechanisms of Polygonum multiflorum Thunb. in Mitigating Ischemic Stroke: A Network Pharmacology and Molecular Docking Study.

Polygonum multiflorum Thunb. (PMT) has shown promise in exerting cerebrovascular protective effects, and its potential for treating ischemic stroke (IS) has garnered attention. However, the lack of clarity regarding its chemical constituents and mechanisms has significantly hindered its clinical application. In this study, we employed network pharmacology and molecular docking techniques for the first time to elucidate the potential compounds and targets of PMT in treating IS. The databases CTD, DrugBank, DisGeNET, GeneCards, OMIM, TTD, PGKB, NCBI, TCMIP, CNKI, PubMed, ZINC, STITCH, BATMAN, ETCM and Swiss provided information on targets related to IS and components of PMT, along with their associated targets. We constructed "compound-target" and protein-protein interaction (PPI) networks sourced from the STRING database using the Cytoscape software. Gene Ontology (GO) enrichment analysis and KEGG pathway analysis were conducted using the DAVID database. Molecular docking between core targets and active compounds was conducted using Autodock4 software. Experiments were performed in an oxygen-glucose deprivation and reperfusion (OGD/R) model to validate the anti-IS activity of compounds isolated from PMT preliminarily. Network pharmacological analysis revealed 16 core compounds, including resveratrol, polydatin, TSG, ω- hydroxyemodin, emodin anthrone, tricin, moupinamide, and others, along with 11 high-degree targets, such as PTGS1, PTGS2, ADORA1, ADORA2, CA1, EGFR, ESR1, ESR2, SRC, MMP3 and MMP9. GO and KEGG enrichment analyses revealed the involvement of HIF-1, Akt signaling pathway and energy metabolism-related signaling pathways. Molecular docking results emphasized eight key compounds and confirmed their interactions with corresponding targets. In vitro OGD/R model experiments identified TSG and tricin as the primary active substances within PMT for its anti-stroke activity. This study contributes new insights into the potential development of PMT for stroke prevention and treatment.

Brain-inspired modular echo state network for EEG-based emotion recognition.

Previous studies have successfully applied a lightweight recurrent neural network (RNN) called Echo State Network (ESN) for EEG-based emotion recognition. These studies use intrinsic plasticity (IP) and synaptic plasticity (SP) to tune the hidden reservoir layer of ESN, yet they require extra training procedures and are often computationally complex. Recent neuroscientific research reveals that the brain is modular, consisting of internally dense and externally sparse subnetworks. Furthermore, it has been proved that this modular topology facilitates information processing efficiency in both biological and artificial neural networks (ANNs). Motivated by these findings, we propose Modular Echo State Network (M-ESN), where the hidden layer of ESN is directly initialized to a more efficient modular structure. In this paper, we first describe our novel implementation method, which enables us to find the optimal module numbers, local and global connectivity. Then, the M-ESN is benchmarked on the DEAP dataset. Lastly, we explain why network modularity improves model performance. We demonstrate that modular organization leads to a more diverse distribution of node degrees, which increases network heterogeneity and subsequently improves classification accuracy. On the emotion arousal, valence, and stress/calm classification tasks, our M-ESN outperforms regular ESN by 5.44, 5.90, and 5.42%, respectively, while this difference when comparing with adaptation rules tuned ESNs are 0.77, 5.49, and 0.95%. Notably, our results are obtained using M-ESN with a much smaller reservoir size and simpler training process.

Total cucurbitacins from Herpetospermum pedunculosum pericarp do better than Hu-lu-su-pian (HLSP) in its safety and hepatoprotective efficacy.

The pericarp of Herpetospermum pedunculosum (HPP) has traditionally been used for treating jaundice and hepatitis. However, the specific hepatoprotective components and their safety/efficacy profiles remain unclear. This study aimed to characterize the total cucurbitacins (TCs) extracted from HPP and evaluate their hepatoprotective potential. As a reference, Hu-lu-su-pian (HLSP), a known hepatoprotective drug containing cucurbitacins, was used for comparison of chemical composition, effects, and safety. Molecular networking based on UHPLC-MS/MS identified cucurbitacin B, isocucurbitacin B, and cucurbitacin E as the major components in TCs, comprising 70.3%, 26.1%, and 3.6% as determined by RP-HPLC, respectively. TCs treatment significantly reversed CCl4-induced metabolic changes associated with liver damage in a dose-dependent manner, impacting pathways including energy metabolism, oxidative stress and phenylalanine metabolism, and showed superior efficacy to HLSP. Safety evaluation also showed that TCs were safe, with higher LD50 and no observable adverse effect level (NOAEL) values than HLSP. The median lethal dose (LD50) and NOAEL values of TCs were 36.21 and 15 mg/kg body weight (BW), respectively, while the LD50 of HLSP was 14 mg/kg BW. In summary, TCs extracted from HPP demonstrated promising potential as a natural hepatoprotective agent, warranting further investigation into synergistic effects of individual cucurbitacin components.

4-octyl itaconate protects against oxidative stress-induced liver injury by activating the Nrf2/Sirt3 pathway through AKT and ERK1/2 phosphorylation.

4-octyl itaconate (4-OI) is a cell-permeable itaconate derivative with anti-inflammatory and antioxidant properties. However, its therapeutic potential for oxidative stress-induced liver injury remains unknown. This study investigated the hepatoprotective effects and mechanisms of 4-OI against oxidative damage in in vitro and in vivo models. 4-OI attenuated H2O2-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction in L02 and HepG2 cells. Untargeted metabolomics profiling and pathway analysis identified the PI3K/AKT/mTOR and MAPK pathways as key regulators of 4-OI's protective effects. Specifically, 4-OI induced phosphorylation of AKT and ERK1/2, leading to activation of the Nrf2 signaling pathway. Nrf2 upregulated expression of the mitochondrial deacetylase Sirt3, which subsequently alleviated H2O2-induced cell injury. In mice, 4-OI reduced acetaminophen (APAP)-induced liver injury as evidenced by attenuated hepatocellular necrosis and decreased serum liver enzymes. It also elevated hepatic expression of Nrf2, Sirt3, p-AKT and p-ERK1/2. Inhibition of AKT, ERK1/2 or Nrf2 blocked the protective effects of 4-OI in vitro, suggesting its antioxidant activity is mediated by activating the Nrf2/Sirt3 pathway via AKT and ERK1/2 phosphorylation. In summary, 4-OI exerted antioxidant and hepatoprotective effects by activating the Nrf2/Sirt3 signaling pathway through AKT and ERK1/2 phosphorylation, which were elucidated using in vitro and in vivo oxidative stress models. This provides novel insights into the mechanisms of 4-OI against oxidative stress-related liver diseases.

Study on the acute toxicity of trichlorfon and its breakdown product dichlorvos to goldfish (Carassius auratus) based on 1H NMR metabonomics.

Trichlorfon, one of the most widely used organophosphate insecticides, is commonly employed in aquaculture and agriculture to combat parasitic infestations. However, its inherent instability leads to rapid decomposition into dichlorvos (DDVP), increasing its toxicity by eightfold. Therefore, the environmental effects of trichlorfon in real-world scenarios involve the combined effects of trichlorfon and its degradation product, DDVP. In this study, we systematically investigated the degradation of trichlorfon in tap water over time using HPLC and LC-MS/MS analysis. Subsequently, an experiment was conducted to assess the acute toxicity of trichlorfon and DDVP on goldfish (Carassius auratus), employing a 1H NMR-based metabolic approach in conjunction with serum biochemistry, histopathological inspection, and correlation network analysis. Exposure to trichlorfon and its degradation product DDVP leads to increased lipid peroxidation, reduced antioxidant activity, and severe hepatotoxicity and nephrotoxicity in goldfish. Based on the observed pathological changes and metabolite alterations, short-term exposure to trichlorfon significantly affected the liver and kidney functions of goldfish, while exerting minimal influence on the brain, potentially due to the presence of the blood-brain barrier. The changes in the metabolic profile indicated that trichlorfon and DDVP influenced several pathways, including oxidative stress, protein synthesis, energy metabolism, and nucleic acid metabolism. This study demonstrated the applicability and potential of 1H NMR-based metabonomics in pesticide environmental risk assessment, providing a feasible method for the comprehensive study of pesticide toxicity in water environments.

Hepialiamides A-C: Aminated Fusaric Acid Derivatives and Related Metabolites with Anti-Inflammatory Activity from the Deep-Sea-Derived Fungus Samsoniella hepiali W7.

A systematic investigation combined with a Global Natural Products Social (GNPS) molecular networking approach, was conducted on the metabolites of the deep-sea-derived fungus Samsoniella hepiali W7, leading to the isolation of three new fusaric acid derivatives, hepialiamides A-C (1-3) and one novel hybrid polyketide hepialide (4), together with 18 known miscellaneous compounds (5-22). The structures of the new compounds were elucidated through detailed spectroscopic analysis. as well as TD-DFT-based ECD calculation. All isolates were tested for anti-inflammatory activity in vitro. Under a concentration of 1 µM, compounds 8, 11, 13, 21, and 22 showed potent inhibitory activity against nitric oxide production in lipopolysaccharide (LPS)-activated BV-2 microglia cells, with inhibition rates of 34.2%, 30.7%, 32.9%, 38.6%, and 58.2%, respectively. Of particularly note is compound 22, which exhibited the most remarkable inhibitory activity, with an IC50 value of 426.2 nM.

Torachrysone-8-O-ß-d-glucoside mediates anti-inflammatory effects by blocking aldose reductase-catalyzed metabolism of lipid peroxidation products.

Aldose reductase (AR) is an important enzyme involved in the reduction of various aldehyde and carbonyl compounds, including the highly reactive and toxic 4-hydroxynonenal (4-HNE), which has been linked to the progression of various pathologies such as atherosclerosis, hyperglycemia, inflammation, and tumors. AR inhibitors have potential therapeutic benefits for these diseases by reducing lipid peroxidation and mitigating the harmful effects of reactive aldehydes. In this study, we found that torachrysone-8-O-ß-d-glucoside (TG), a natural product isolated from Polygonum multiflorum Thunb., functions as an effective inhibitor of AR, exhibiting potent effects in clearing reactive aldehydes and reducing inflammation. TG up-regulated the mRNA levels of several antioxidant factors downstream of NRF2, especially glutathione S-transferase (GST), which is significantly increased, thus detoxifying 4-HNE by facilitating the conjugation of 4-HNE to glutathione, forming glutathione-4-hydroxynonenal (GS-HNE). By employing a combination of molecular docking, cellular thermal shift assay, and enzyme activity experiments, we demonstrated that TG exhibited strong binding affinity with AR and inhibited its activity and blocked the conversion of GS-HNE to glutathionyl-1,4-dihydroxynonene (GS-DHN), thereby preventing the formation of protein adducts and inducing severe cellular damage. This study provides novel insights into the anti-inflammatory mechanisms of AR inhibitors and offers potential avenues for developing therapeutic strategies for AR-related pathologies. Our findings suggest that TG, as an AR inhibitor, may hold promise as a therapeutic agent for treating conditions characterized by excessive lipid peroxidation and inflammation. Further investigations are needed to fully explore the clinical potential of TG and evaluate its efficacy in the treatment and management of these complex diseases.

Peptide OA-VI12 restrains melanogenesis in B16 cells and C57B/6 mouse ear skin via the miR-122-5p/Mitf/Tyr axis.

Excessive melanogenesis leads to hyperpigmentation, which is one of the common skin conditions in humans. Existing whitening cosmetics cannot meet market needs due to their inherent limitations. Thus, the development of novel skin-whitening agents continues to be a challenge. The peptide OA-VI12 from the skin of amphibians at high altitude has attracted attention due to its remarkable anti light damage activity. However, whether OA-VI12 has the skin-whitening effect of inhibiting melanogenesis is still. Mouse melanoma cells (B16) were used to study the effect of OA-VI12 on cell viability and melanin content. The pigmentation model of C57B/6 mouse ear skin was induced by UVB and treated with OA-VI12. Melanin staining was used to observe the degree of pigmentation. MicroRNA sequencing, quantitative real-time PCR (qRT-PCR), immunofluorescence analysis and Western blot were used to detect the change of factor expression. Double luciferase gene report experiment was used to prove the regulatory relationship between miRNA and target genes. OA-VI12 has no effect on the viability of B16 cells in the concentration range of 1-100 µM and significantly inhibits the melanin content of B16 cells. Topical application of OA-VI12, which exerted transdermal potency, prevented UVB-induced pigmentation of ear skin. MicroRNA sequencing and double luciferase reporter analysis results showed that miR-122-5p, which directly regulated microphthalmia-associated transcription factor (Mitf), had significantly different expression before and after treatment with OA-VI12. Mitf is a simple helix loop and leucine zipper transcription factor that regulates tyrosinase (Tyr) expression by binding to the M-box promoter element of Tyr. qRT-PCR, immunofluorescence analysis and Western blot showed that OA-VI12 up-regulated the expression of miR-122-5p and inhibited the expression of Mitf and Tyr. The effects of OA-VI12 on melanogenesis inhibition in vitro and in vivo may involve the miR-122-5p/Mitf/tyr axis. OA-VI12 represents the first report on a natural amphibian-derived peptide with skin-whitening capacity and the first report of miR-122-5p as a target for regulating melanogenesis, thereby demonstrating its potential as a novel skin-whitening agent and highlighting amphibian-derived peptides as an underdeveloped resource.

Maintaining immune homeostasis with Coptis Chinensis water extract to mitigate sepsis severity via modulating gut microbiome and metabolism.

Sepsis arises from an uncontrolled inflammatory response to infection that can lead to organ failure. The gut microbiome is increasingly recognized as a key modulator of sepsis progression. This study investigated whether Coptis chinensis water extract (CCWE) could attenuate sepsis by modulating the gut microbiome and immune response. A rat model of sepsis induced by cecum ligation and perforation was used. 16 S ribosomal ribonucleic acid (rRNA) sequencing, proton nuclear magnetic resonance (1H NMR) metabolomics and flow cytometry assays were used to evaluate microbial, metabolic and immune profiles. CCWE treatment reversed sepsis-induced loss of beneficial bacteria like Firmicutes and Bacteroidetes and restored gut microbial balance. CCWE increased short-chain fatty acids, carnitine and phenylacetate, which provide energy and curb inflammation. By enhancing immune homeostasis and maintaining regulatory T cells (Tregs), CCWE treatment also exerted bidirectional regulation on T cells for initially suppressing hyperactivation then enabling recovery. Overall, CCWE may benefit sepsis by regulating the gut-microbiome-immune axis. By restoring microbiome balance, improving metabolism, and modulating immunity, CCWE treatment shows potential for alleviating sepsis severity and progression. The increases in beneficial bacteria, Tregs, and anti-inflammatory metabolites coupled with decreases in opportunistic pathogens likely contributed collectively to CCWE's protective effects. CCWE may emerge as an alternative or adjunctive option for managing disorders of dangerous inflammation like sepsis. Future research should explore CCWE's mechanisms of action clinically to determine its potential as a safe, effective means of modulating health through natural regulation of the gut microbiome and immune function.

Root damage of street trees in urban environments: An overview of its hazards, causes, and prevention and control measures.

Root damage from urban street trees represents a substantial concern arising from the conflict between root growth and limited growth spaces. Nonetheless, the phenomenon of root damage, which threatens the safety of urban facilities, appears to have received little scholarly attention. Moreover, the effectiveness of some proposed measures for root damage prevention and control has not yet received consistent evaluation. Accordingly, this review aims to examine root damage, including its causes and available prevention and control measures. Urban trees are found to have a high potential to exert root damage on infrastructures when the following factors exist. These include large and mature tree, fast-growing trees, trees planted in limited soil volumes, shallow-rooted tree with buttress roots, trees whose diameter at breast height exceeds 10 cm, old and cracked road paving, high soil surface moisture content, short distances between trees and sidewalks (<2 to 3 m), and underground pipes that are already broken and made of metals or stones. The phenotypic traits of trees may be the primary factor causing root damage when there is a mismatch between the root-soil requirements of urban street trees and the actual soil environment. The poor effectiveness of root damage prevention and control measures may be attributed to the lack of connection between the development of control measures and the mechanism of root damage.

Therapeutic efficacy and underlying mechanisms of Gastrodia elata polysaccharides on dextran sulfate sodium-induced inflammatory bowel disease in mice: Modulation of the gut microbiota and improvement of metabolic disorders.

Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disease, and an imbalance in the gut microbiota is a critical factor in its development. Gastrodia elata (G. elata), an Orchidaceae plant, is recognized for its nutritional and medicinal value. Studies have shown that G. elata polysaccharides (GBP) have anti-inflammatory properties that may ameliorate IBD. However, the therapeutic effects of GBP on gut microbiota metabolism remain unknown. Therefore, we aimed to examine the therapeutic potential of G. elata extract and GBP in dextran sulfate sodium (DSS)-induced IBD mice. GBP demonstrated the best therapeutic effect by reducing IBD symptoms in mice to the greatest extent. Administering GBP resulted in significant increases in the relative abundances of bacteria with potential anti-inflammatory effects, such as Ligilactobacillus and Alloprevotella, and decreases in the levels of bacteria associated with proinflammatory responses, such as Bacteroides and Escherichia-Shigella. Furthermore, 36 significant differential metabolites between the model and GBP groups were identified in feces, which were mainly enriched in amino acid metabolism, including tryptophan and cysteine, vitamin B6 metabolism and steroid hormone biosynthesis. Consequently, investigating the metabolic regulation of the gut microbiota is a promising approach to evaluate the therapeutic effect of GBP on IBD.

A novel transformer-based ECG dimensionality reduction stacked auto-encoders for arrhythmia beat detection.

BACKGROUND: Electrocardiogram (ECG) is a powerful tool for studying cardiac activity and diagnosing various cardiovascular diseases, including arrhythmia. While machine learning and deep learning algorithms have been applied to ECG interpretation, there is still room for improvement. For instance, the commonly used Recurrent Neural Networks (RNNs), reply on its previous state to update and is therefore ineffective for parallel computing. RNN also struggles to efficiently address the issue of long-distance reliance. PURPOSE: To reduce computational complexity by dimensionality reduction of ECG signals we constructed a Stacked Auto-encoders model using Transformer for ECG-based arrhythmia detection. And overcome the challenges of long-term dependencies and limited parallelizability in traditional RNNs when applied to ECG signal processing. METHODS: In this paper, a Transformer-Based ECG Dimensionality Reduction Stacked Auto-encoders model is proposed for ECG-based arrhythmia detection. The transformer is used to encode ECG signals into a feature matrix, which is then dimensionally reduced using unsupervised greedy training through the four linear layers. This resulted in a low-dimensional representation of ECG features, which are subsequently classified using support vector machines (SVM) to minimize overfitting. RESULTS: The proposed method is benchmarked on the MIT-BIH Arrhythmia database. In the 10-fold cross validation of beat-based arrhythmia detection, the average accuracy, sensitivity, specificity and F1 score of the proposed method are 99.83%, 98.84%, 99.84% and 99.13%, respectively, for the record-based arrhythmia detection which refers to the approach where the training and testing sets use ECG data from independent recorded patients are 88.10%, 49.79%, 91.56% and 39.95%, respectively. CONCLUSIONS: Compared to other existing ECG-based arrhythmia detection methods, our proposed approach exhibits improved detection accuracy and stronger generalization for arrhythmia beats. Additionally, the use of the record-based data division method makes our approach more suitable for clinical practice.

The innate immune sensor STING accelerates neointima formation via NF-κB signaling pathway.

Vascular smooth muscle cells (VSMCs) proliferation, migration, and phenotypic switching are considered crucial events in the progression of neointima formation. Stimulator of interferon genes (STING), an innate immune sensor of cyclic dinucleotides against pathogens, in neointima formation remains obscure. Here, we observed a significant increase in STING expression on the neointima of injured vessels and mouse aortic VSMCs induced by PDGF-BB. In vivo, global knockout of STING (Sting-/-) attenuated neointima formation after vascular injury. In vitro data showed that STING deficiency significantly alleviated PDGF-BB-induced proliferation and migration in VSMCs. Furthermore, these contractile marker genes were upregulated in Sting-/- VSMCs. Overexpression of STING promoted proliferation, migration, and phenotypic switching in VSMCs. Mechanistically, STING-NF-κB signaling was involved in this process. The pharmacological inhibition of STING induced by C-176 partially prevented neointima formation due to suppression of VSMCs proliferation. Taken together, STING-NF-κB axis significantly promoted proliferation, migration, and phenotypic switching of VSMCs, which may be a novel therapeutic approach to combat vascular proliferative diseases.

Novel uniplanar pedicle screw systems applied to thoracolumbar fractures: a biomechanical study.

Objective: In this study, the advantages of the internal fixation configuration composed of uniplanar pedicle screws in the treatment of thoracolumbar fractures were verified by biomechanical experimental methods, which provided the basis for subsequent clinical experiments and clinical applications. Methods: A total of 24 fresh cadaveric spine specimens (T12-L2) were utilized to conduct biomechanical experiments. Two different internal fixation configurations, namely, the 6-screw configuration and the 4-screw/2-NIS (new intermediate screws) configuration, were tested using fixed-axis pedicle screws (FAPS), uniplanar pedicle screws (UPPS), and polyaxial pedicle screws (PAPS) respectively. The spine specimens were uniformly loaded with 8NM pure force couples in the directions of anteflexion, extension, left bending, right bending, left rotation, and right rotation, and the range of motion (ROM) of the T12-L1 and L1-L2 segments of the spine was measured and recorded to access biomechanical stability. Results: No structural damage such as ligament rupture or fracture occurred during all experimental tests. In the 6-screw configuration, the ROM of the specimens in the UPPS group was significantly better than that of the PAPS group but weaker than those of the FAPS group (p < 0.01). In the 4-screw/2-NIS configuration, the results were identical to the biomechanical test results for the 6-screw configuration (p < 0.01). Conclusion: Biomechanical test results show that the internal fixation configuration with UPPS can maintain the stability of the spine well, and the results are better than that of PAPS. UPPS has both the biomechanical advantages of FAPS and the superiority of easy operation of PAPS. We believe it is an optional internal fixation device for minimally invasive treatment of thoracolumbar fractures.

Trophic transfer of silver nanoparticles shifts metabolism in snails and reduces food safety.

Food security and sustainable development of agriculture has been a key challenge for decades. To support this, nanotechnology in the agricultural sectors increases productivity and food security, while leaving complex environmental negative impacts including pollution of the human food chains by nanoparticles. Here we model the effects of silver nanoparticles (Ag-NPs) in a food chain consisting of soil-grown lettuce Lactuca sativa and snail Achatina fulica. Soil-grown lettuce were exposed to sulfurized Ag-NPs via root or metallic Ag-NPs via leaves before fed to snails. We discover an important biomagnification of silver in snails sourced from plant root uptake, with trophic transfer factors of 2.0-5.9 in soft tissues. NPs shifts from original size (55-68 nm) toward much smaller size (17-26 nm) in snails. Trophic transfer of Ag-NPs reprograms the global metabolic profile by down-regulating or up-regulating metabolites for up to 0.25- or 4.20- fold, respectively, relative to the control. These metabolites control osmoregulation, phospholipid, energy, and amino acid metabolism in snails, reflecting molecular pathways of biomagnification and pontential adverse biological effects on lower trophic levels. Consumption of these Ag-NP contaminated snails causes non-carcinogenic effects on human health. Global public health risks decrease by 72% under foliar Ag-NP application in agriculture or through a reduction in the consumption of snails sourced from root application. The latter strategy is at the expense of domestic economic losses in food security of $177.3 and $58.3 million annually for countries such as Nigeria and Cameroon. Foliar Ag-NP application in nano-agriculture has lower hazard quotient risks on public health than root application to ensure global food safety, as brought forward by the United Nations Sustainable Development Goals.

A short peptide exerts neuroprotective effects on cerebral ischemia-reperfusion injury by reducing inflammation via the miR-6328/IKKß/NF-κB axis.

BACKGROUND: Despite considerable efforts, ischemic stroke (IS) remains a challenging clinical problem. Therefore, the discovery of effective therapeutic and targeted drugs based on the underlying molecular mechanism is crucial for effective IS treatment. METHODS: A cDNA-encoding peptide was cloned from RNA extracted from Rana limnocharis skin, and the mature amino acid sequence was predicted and synthesized. Hemolysis and acute toxicity of the peptide were tested. Furthermore, its neuroprotective properties were evaluated using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in neuron-like PC12 cells. The underlying molecular mechanisms were explored using microRNA (miRNA) sequencing, quantitative real-time polymerase chain reaction, dual-luciferase reporter gene assay, and western blotting. RESULTS: A new peptide (NP1) with an amino acid sequence of 'FLPAAICLVIKTC' was identified. NP1 showed no obvious toxicities in vivo and in vitro and was able to cross the blood-brain barrier. Intraperitoneal administration of NP1 (10 nmol/kg) effectively reduced the volume of cerebral infarction and relieved neurological dysfunction in MCAO/R model rats. Moreover, NP1 significantly alleviated the decrease in viability and increase in apoptosis of neuron-like PC12 cells induced by OGD/R. NP1 effectively suppressed inflammation by reducing interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) levels in vitro and in vivo. Furthermore, NP1 up-regulated the expression of miR-6328, which, in turn, down-regulated kappa B kinase ß (IKKß). IKKß reduced the phosphorylation of nuclear factor-kappa B p65 (NF-κB p65) and inhibitor of NF-κB (I-κB), thereby inhibiting activation of the NF-κB pathway. CONCLUSIONS: The newly discovered non-toxic peptide NP1 ('FLPAAICLVIKTC') exerted neuroprotective effects on cerebral ischemia-reperfusion injury by reducing inflammation via the miR-6328/IKKß/NF-κB axis. Our findings not only provide an exogenous peptide drug candidate and endogenous small nucleic acid drug candidate but also a new drug target for the treatment of IS. This study highlights the importance of peptides in the development of new drugs, elucidation of pathological mechanisms, and discovery of new drug targets.

Hypoxia and TNF-α Synergistically Induce Expression of IL-6 and IL-8 in Human Fibroblast-like Synoviocytes via Enhancing TAK1/NF-κB/HIF-1α Signaling.

Hypoxia and increased levels of inflammatory cytokines in the joints are characteristics of rheumatoid arthritis (RA). However, the effects of hypoxia and tumor necrosis factor-α (TNF-α) on interleukin (IL)-6 and IL-8 production on fibroblast-like synoviocytes (FLSs) remain to be clarified. This study aimed to explore how hypoxia and TNF-α affect the expression of IL-6 and IL-8 in human FLSs isolated from RA patients. Hypoxia or TNF-α treatment alone significantly increased the expression and promoter activity of IL-6, IL-8, and hypoxia-inducible factor-1α (HIF-1α). Treatment of hypoxic FLSs with TNF-α further significantly elevated the expression of these cytokines and enhanced promoter activity of HIF-1α, which was abrogated by treatment with the HIF-1α inhibitor YC-1. Similarly, TNF-α alone elevated the phosphorylation and promoter activity of nuclear factor-κBp65 (NF-κBp65) in the FLSs. These effects were further enhanced by the combined treatment of hypoxia and TNFα but were attenuated by the NF-κB inhibitor BAY11-7082. NF-κB-p65 inhibition decreased the effect of TNF-α on HIF-1α upregulation in the FLSs in response to hypoxia. The combination of hypoxia and TNF-α also significantly upregulated transforming growth factor-ß-activated kinase 1 (TAK1) expression, and silencing TAK1 dramatically decreased NF-κB-p65, HIF-1α, IL-6, and IL-8 expression under the same conditions. Our results indicate that hypoxia and TNF-α synergistically increase IL-6 and IL-8 expression in human FLSs via enhancing TAK1/NF-κB/HIF-1α signaling.

Finite element analysis of different medial fixation strategies in double-plate osteosynthesis for AO type 33-C2 Femoral fractures.

OBJECTIVES: In this study, we evaluated the biomechanical characteristics of different locations of medial fixation strategies in double-plate osteosynthesis for fixing AO/ASIF type 33-C2 femoral fractures by means of finite element analysis. METHODS: We used 3-matic software and UG-NX software to construct AO/ASIF type 33-C2 Femoral fractures and lateral less invasive stabilization system (LISS) plates, medial plates (MPs), and medial support pads (MSPs), respectively. Then, the LISS, MP and MSP were assembled into the fracture model separately to form three fixation models: MSP+LISS, anteromedial plate (AMP+LISS), and MP+LISS. In the next procedure, we performed finite element analysis using ANSYS software after meshing the elements of the models in HyperMesh 11.0 software. Loading conditions including lateral-medial four-point bending, anterior-posterior four-point bending, axial loading, and torsional loading were applied to evaluate the biomechanical advantages among the three fixation types. We observed the peak Von Mises Stress (VMS) value, maximum displacement, bending angle in the coronal plane of the fracture, and torsional angle of the fracture to assess the degree of plate deformation and fixation stability. RESULTS: Our results showed that in both lateral-medial four-point bending and anterior-posterior four-point bending, the calculations of MP+LISS were marginally better than those of AMP+LISS. However, with the action of axial loading and torsional loading, the deformation of MP+LISS was distinctly smaller than that of AMP+LISS, and the fixation stability of MP+LISS was also prominently better. Under lateral-medial four-point bending, the VMS on the lateral plate of MSP+LISS (59.977 MPa) was approximately half of the two double-plate models. Under anterior and posterior four-point bending, the 38.209 MPa peak VMS of MSP+LISS was still superior to the other two double-plate models. Under torsional loading, the peak VMS (347.75 MPa), the maximum torsional angle of the femoral head (7.852 °), and the torsional angle of fracture (0.036 °) of MSP+LISS preceded those of the other two models. However, under axial loading, the peak VMS (76.376 MPa) and the maximum displacement (3.1798 mm) of MSP+LISS were slightly higher than those of MP+LISS. CONCLUSION: The MSP+LISS model showed better biomechanical performance than the double-plate models, which might be an effective solution for the treatment of comminuted distal femur fractures.