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Objective: To explore the mechanisms of the TGF-ß1/Smad and NF-κB pathways in the effect of berberine (BBR) on colon cancer epithelial-mesenchymal transition (EMT) and their regulatory relationships with microRNAs (miRNAs). Methods: TGF-ß1 was used to induce EMT in normal colon epithelial HCoEpiC cells and colon cancer HT29 cells in vitro. After BBR intervention, the expression of EMT-related markers and the major molecules involved in the TGF-ß1/Smad and NF-κB pathways were detected via western blotting. Cell migration was detected via wound healing assays. SMAD2 and NF-κB p65 were overexpressed and transfected into cells, and the inhibitors SB431542 and BAY 11-7082 were added to block the TGF-ß1/Smad and NF-κB pathways, respectively. The mRNA expression levels of related microRNA genes were detected by using RT‒PCR. Results: Treatment with 10 ng/ml TGF-ß1 for 72 h significantly induced EMT in HCoEpiC and HT29 cells, which was repressed by BBR. BBR significantly inhibited the TGF-ß1-induced migration of HCoEpiC and HT29 cells and the TGF-ß1-promoted expression of p-Smad2/3, NF-κB p65, and p-IκBα. Compared to those in the group treated with TGF-ß1, the expression of NF-κB p65 and p-Smad2 in the group treated with NF-κB pathway inhibitor BAY 11-7082 was decreased (P < 0.05), and TGF-ß1 signalling inhibitor SB431542 significantly reduced the expression of NF-κB p65 (P < 0.05). Overexpression of NF-κB p65 and SMAD2 in HT29 cells decreased the expression of E-cadherin and caused a relative increase in N-cadherin. BBR mediated the expression profile of microRNAs in TGF-ß1-induced HCoEpiC cells, but this pattern differed from that in HT29 cells. SB431542 and BAY 11-7082 significantly reduced the mRNA level of miR-1269a in HCoEpiC and HT29 cells (P < 0.05). Overexpressed NF-κB p65 and SMAD2 increased the mRNA level of miR-1269a in both cell lines; however, this increase was significantly lower than that in the TGF-ß1 treatment group (P < 0.05). Conclusion: BBR can significantly inhibit TGF-ß1-induced EMT in normal and cancerous colon epithelial cells through the inhibition of the TGF-ß1/Smad and NF-κB p65 pathways. TGF-ß1/Smads can promote the NF-κB p65 pathway, which is a common target of miR-1269a, and can partially regulate the expression of miR-1269a.

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Synergistic photothermal/immunotherapy has garnered significant attention for its potential to enhance tumor therapeutic outcomes. However, the fabrication of an intelligent system with a simple composition that simultaneously exerts photothermal/immunotherapy effect and imaging guidance function still remains a challenge. Herein, a glutathione (GSH)-responsive theranostic nanoprobe, named HA-MnO2/ICG, was elaborately constructed by loading photothermal agent (PTA) indocyanine green (ICG) onto the surface of hyaluronic acid (HA)-modified manganese dioxide nanosheets (HA-MnO2) for magnetic resonance (MR) imaging-guided synergetic photothermal/immuno-enhanced therapy. In this strategy, HA-MnO2 nanosheets were triggered by the endogenous GSH in tumor microenvironment to generate Mn2+ for MR imaging, where the longitudinal relaxation rate of HA-MnO2/ICG was up to 14.97 mM-1s-1 (∼24 times than that found in a natural environment), demonstrating excellent intratumoral MR imaging. Moreover, the HA-MnO2/ICG nanoprobe demonstrates remarkable photothermal therapy (PTT) efficacy, generating sufficient heat to induce immunogenic cell death (ICD) within tumor cells. Meanwhile the released Mn2+ ions from the nanosheets function as potent immune adjuvants, amplifying the immune response against cancer. In vivo experiments validated that HA-MnO2/ICG-mediated PTT was highly effective in eradicating primary tumors, while simultaneously enhancing immunogenicity to prevent the growth of distal metastasis. This hybrid HA-MnO2/ICG nanoprobe opened new avenues in the design of MR imaging-monitored PTT/immuno-enhanced synergistic therapy for advanced cancer.

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Chelidonii herba is a traditional Chinese medicinal herb with effects including antispasmodic, analgesic, antitussive, and bronchodilator properties. Alkaloids are the main bioactive ingredients in Chelidonii herba. In this study, a two-dimensional nuclear magnetic resonance (Heteronuclear Singular Quantum Correlation, HSQC-2D-NMR) technique was employed to quantitatively analyze the total alkaloid content and three major active alkaloid monomers in Chelidonii herba from eleven different sources. The quantification results of the three monomeric alkaloids were also verified using conventional quantitative control methods such as HPLC. Experimental findings indicate that the total alkaloid content is not directly correlated with the content of the three monomeric alkaloids. Furthermore, the content of any individual monomeric alkaloid does not accurately reflect the overall quality of Chelidonii herba. It was demonstrated that the 2D-Q-NMR NMR can be applied as an alternative method. While maintaining the same levels of accuracy and precision, the 2D-Q-NMR method is simpler to operate and provides more comprehensive results with higher reproducibility in some cases.

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The Volatile Organic Compounds (VOCs) in asphalt fume is widely concerned currently due to its biological toxicity, while the negative effects by asphalt Gaseous Inorganic Compounds (GICs) have not been well quantified and addressed yet. The study investigated the thermodynamic characteristics of base and modified asphalt binders during the multiple phases of releasing the GICs, then the releasing amounts and concentrations of GICs were quantified by fume analyzer. Meanwhile, the environmental impacts of GICs from 4 kinds of asphalt binders have been quantified and interpreted. The results showed that the modified asphalt released less proportion of GICs than base asphalt as heated by same thermal condition according to the TG-DTG and enthalpy analysis. Considering 1 g of asphalt sample, the base asphalt could release extra 8 mg of GICs than modified asphalt, additionally, the emissions of NO2, NO, CO2, and SO2 are all less than the mass of 1 mg. For the environmental effects, the releasing GICs had the greatest impacts on human toxicity due to the intensive CO emission. These results are expected to provide reference and new insights into the improvement of asphalt fumes mitigation.

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INTRODUCTION: Small cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC). METHODS: Patients received up to six 21-day cycles of etoposide (100 mg/m2, days 1-3) and cisplatin (80 mg/m2, day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose. RESULTS: Twenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage. CONCLUSIONS: Cediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity.

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Predictors for coronavirus disease 2019 (COVID-19)-specific and non-COVID-19-specific deaths have not been extensively studied. This cohort study in Taiwan investigated predictors for COVID-19-specific and non-COVID-19-specific deaths among hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. From January to July 2022, 2196 COVID-19 patients at Taipei City Hospital were consecutively recruited in this cohort study. Among the 175 deceased COVID-19 patients, 147 (84.0%) and 28 (16.0%) had COVID-19-specific and non-COVID-19-specific deaths, respectively. After controlling for other covariates, multinomial logistic regressions showed that age ≥ 65 was significantly associated with higher risks for both COVID-19-specific, adjusted odds ratio (AOR) = 6.21; 95% confidence interval (CI) [3.12, 12.35]; and non-COVID-19-specific deaths (AOR = 6.06; 95% CI [1.34, 27.34]). Fully vaccinated individuals (AOR = 0.50; 95% CI [0.33, 0.74]) and Paxlovid recipients (AOR = 0.45; 95% CI [0.20, 0.98]) had lower COVID-19-specific death risks, while comorbid cancer or end-stage renal disease patients faced higher risks of non-COVID-19-specific deaths. Our study findings suggest that vaccination and Paxlovid treatment are crucial for reducing SARS-CoV-2-specific mortalities, while comorbid patients need careful monitoring to reduce non-COVID-19-specific deaths.

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Myasthenia gravis (MG) and idiopathic inflammatory myopathy (IIM) are autoimmune diseases of the nervous system, and their main clinical manifestation is muscle weakness. The concurrent presence of both conditions in the same patient is clinically rare and easily missed. Here, we report the case of a 74-year-old woman who went to the doctor with fluctuating weakness of the limbs and muscle pain. By analyzing the patient's history and the results of repeated frequency electrical stimulation, chest computed tomography, thigh muscle magnetic resonance imaging, serum antibody detection, lymph node biopsy, etc., she was finally diagnosed with MG-concomitant IIM with squamous cell carcinoma of the thymus. Acetylcholine receptor antibody, titin antibody, ryanodine receptor antibody, anti-JO-1 antibody, and Ro-52 antibody tests were positive. MG-concomitant IIM is often associated with thymoma. The immunopathology mechanism may be different from that of pure MG or IIM, which needs further research.

Assuntos

Autoanticorpos , Miastenia Gravis , Miosite , Timoma , Neoplasias do Timo , Humanos , Miastenia Gravis/imunologia , Miastenia Gravis/complicações , Miastenia Gravis/diagnóstico , Feminino , Timoma/complicações , Timoma/imunologia , Timoma/diagnóstico , Idoso , Miosite/imunologia , Miosite/diagnóstico , Miosite/complicações , Autoanticorpos/sangue , Autoanticorpos/imunologia , Neoplasias do Timo/complicações , Neoplasias do Timo/imunologia , Neoplasias do Timo/diagnóstico

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RNA editing is an important post-transcriptional event in all living cells. Within chloroplasts and mitochondria of higher plants, RNA editing involves the deamination of specific cytosine (C) residues in precursor RNAs to uracil (U). An increasing number of recent studies detail specificity of C-to-U RNA editing as an essential prerequisite for several plant stress-related responses. In this review, we summarize the current understanding of responses and functions of C-to-U RNA editing in plants under various stress conditions to provide theoretical reference for future research.

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Tomato fruit colors are directly associated with their appearance quality and nutritional value. However, tomato fruit color formation is an intricate biological process that remains elusive. In this work we characterized a tomato yellow fruited tomato 3 (yft3, e9292, Solanum lycopersicum) mutant with yellow fruits. By the map-based cloning approach, we identified a transversion mutation (A2117C) in the YFT3 gene encoding a putative isopentenyl diphosphate isomerase (SlIDI1) enzyme, which may function in the isoprenoid biosynthetic pathway by catalyzing conversion between isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The mutated YFT3 (A2117C) (designated YFT3 allele) and the YFT3 genes did not show expression difference at protein level, and their encoded YFT3 allelic (S126R) and YFT3 proteins were both localized in plastids. However, the transcript levels of eight genes (DXR, DXS, HDR, PSY1, CRTISO, CYCB, CYP97A, and NCED) associated with carotenoid synthesis were upregulated in fruits of both yft3 and YFT3 knockout (YFT3-KO) lines at 35 and 47 days post-anthesis compared with the red-fruit tomato cultivar (M82). In vitro and in vivo biochemical analyses indicated that YFT3 (S126R) possessed much lower enzymatic activities than the YFT3 protein, indicating that the S126R mutation can impair YFT3 activity. Molecular docking analysis showed that the YFT3 allele has higher ability to recruit isopentenyl pyrophosphate (IPP), but abolishes attachment of the Mg2+ cofactor to IPP, suggesting that Ser126 is a critical residue for YTF3 biochemical and physiological functions. As a result, the yft3 mutant tomato line has low carotenoid accumulation and abnormal chromoplast development, which results in yellow ripe fruits. This study provides new insights into molecular mechanisms of tomato fruit color formation and development.

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Postoperative adhesion (POA) is a common and serious complication following various types of surgery. Current physical barriers either have a short residence time at the surgical site with a low tissue attachment capacity or are prone to undesired adhesion formation owing to the double-sided adhesive property, which limits the POA prevention efficacy of the barriers. In this study, Janus-structured microgels (Janus-MGs) with asymmetric tissue adhesion capabilities are fabricated using a novel bio-friendly gas-shearing microfluidic platform. The anti-adhesive side of Janus-MGs, which consists of alginate, hyaluronic acid, and derivatives, endows the material with separation, lubrication, and adhesion prevention properties. The adhesive side provided Janus-MGs with tissue attachment and retention capability through catechol-based adhesion, thereby enhancing the in situ adhesion prevention effect. In addition, Janus-MGs significantly reduced blood loss and shortened the hemostatic time in rats, further reducing adhesion formation. Three commonly used rat POA models with different tissue structures and motion patterns are established in this study, namely peritoneal adhesion, intrauterine adhesion, and peritendinous adhesion models, and the results showed that Janus-MGs effectively prevented the occurrence of POA in all the models. The fabrication of Janus-MGs offers a reliable strategy and a promising paradigm for preventing POA following diverse surgical procedures.

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BACKGROUND: Many individuals undergoing surgery involving general anesthesia are asked to fast for a prolonged period to ensure perioperative safety, yet this can initiate stress reactions and insulin resistance, harming postoperative recovery. Such fasting may be particularly problematic for those who have type 2 diabetes. Here we assessed how giving such individuals oral carbohydrates before total knee arthroplasty can affect outcomes. METHODS: We randomized 90 patients who had non-insulin dependent type 2 diabetes mellitus who were scheduled for elective total knee arthroplasty at one medical center between April 2022 and January 2023 to receive oral carbohydrates at 2 or 4 hours before surgery or to receive a carbohydrate-free "placebo" drink at 4 hours before surgery. The three groups were compared in terms of postoperative blood glucose, insulin resistance, ß cell activity, postoperative wound complications, and other clinical outcomes. RESULTS: The group who received oral carbohydrates at 2 or 4 hours before surgery showed significantly lower insulin resistance than the placebo group (group at 2 hours, 9.0 ± 3.4; group at 4 hours, 15.8 ± 6.9 versus placebo, 30.9 ± 10.5, P < 0.001) and lower ß cell activity (207.7 ± 106.7%; group at 4 hours, 243.2 ± 114.9% versus 421.5 ± 209.3%, P < 0.001). Those groups were also significantly less likely than the placebo group to experience preoperative hunger or postoperative hyperglycemia. Among patients who received oral carbohydrates, those who received them 2 hours before surgery showed significantly lower insulin resistance and better glycemic control on postoperative day 1 than those who received carbohydrates 4 hours before surgery. None of the subjects developed intraoperative aspiration or experienced severe postoperative complications. CONCLUSION: Oral carbohydrates at 2 to 4 hours before total knee arthroplasty are safe and can significantly alleviate preoperative hunger while mitigating postoperative insulin resistance and improving glycemic control in patients who have non-insulin-dependent type 2 diabetes mellitus.

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Precisely tuning how and where a reaction occurs in a one-step selective system is important but challenging owing to the similar electronic environments in multiple active sites. In this work, highly selective and effective reaction sites were obtained by generating copper coordination polymers (Cu-CP) of a range of sizes and morphologies, from bulk solid crystals (1) to uniform nanosphere structures (1a), by controlling the amount of surfactant hexadecyl trimethylammonium bromide (CTAB). The results indicated that the morphology and size of the uniform nanosphere structures were affected by the proportion of CTAB; uniform distribution of nanosphere structures was achieved with a premade building carrier when the content of CTAB was 0.005 mmol, generating a well-established platform. Photocatalytic cadmium sulfide (CdS) was then immobilized on the surface of the premade platform unit 1a through an in situ process to generate CdS@1a composites with well-dispersed catalytic CdS active sites. Furthermore, the well-defined CdS@1a composite platform was utilized as photocatalysts to explore the selective one-step depolymerization reaction under blue-light irradiation. Notably, the CdS0.149@1a composite, which featured a unique structure with evenly dispersed, closely spaced catalytic sites, exhibiting remarkable photoelectrochemical behaviors for selective one-step depolymerization of lignin model substances to aromatic monomer phenol and acetophenone framework products. This work demonstrates the use of an inherently morphological process to construct outstanding photocatalysts that could enable a wide range of photocatalytic reactions.

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The rapid expansion of highway infrastructure in the mountainous regions of China has led to a significant increase in tunnel construction, generating substantial amounts of tunnel waste slag. Concurrently, the development of transportation infrastructure has created a critical shortage of natural aggregates, necessitating the exploration of alternative sustainable sources. This study aimed to conduct a comprehensive evaluation of the physical and mechanical properties of tunnel waste slag and explore its potential for utilization in cement-stabilized base courses for highway engineering applications. The uniaxial compressive strength of the parent rock (tunnel waste slag) ranged from 81 MPa to 89 MPa in the desiccated state, indicating its suitability for use as a construction material. This study also determined the maximum dry density (2.432 g/cm3) and optimal moisture content (5.4%) of cement-stabilized mixtures incorporating recycled aggregates derived from tunnel waste slag. The splitting tensile strength of these mixtures at 28 days varied from 0.48 MPa to 0.73 MPa, demonstrating robust mechanical performance. Moreover, the unconfined compressive strength of these mixtures escalated from 7.0 MPa at 7 days to 11.0 MPa at 90 days, signifying a substantial enhancement in strength over time. These results validate the viability of utilizing tunnel waste slag in highway engineering and furnish valuable insights for designers, concrete manufacturers, and construction firms engaged in the development of cement-stabilized aggregate base courses.

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BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, a notable increase in acute macular neuroretinopathy (AMN) cases was observed. This study aimed to investigate the potential association between AMN and COVID-19 by examining 3 cases in China. CASE SUMMARY: The first case involved a 30-year-old man who presented with progressive vision loss following a COVID-19 infection. Optical coherence tomography (OCT) and near-infrared imaging identified hallmark AMN lesions, hyperreflective disruptions within the outer plexiform layer, and hyporeflective anomalies in the ellipsoid zone, leading to an AMN diagnosis. Despite partial visual recovery, OCT angiography (OCTA) revealed persistent microvascular changes, specifically a decreased vascular density in the deep capillary plexus. The second case was a 24-year-old woman who experienced blurred vision and exhibited bilateral cotton-wool spots on fundus examination post-COVID-19. Imaging confirmed the presence of AMN along with paracentral acute middle maculopathy (PAMM). Follow-up OCTA found a progressive reduction in vascular density, indicating ongoing microvascular compromise. The third case was a 28-year-old woman who reported sensations of occlusion in her right eye following a COVID-19 infection. Imaging confirmed both AMN and PAMM, revealing similar decreases of microvascular density on OCTA despite a significant improvement in visual acuity. We noted that all 3 patients had received the COVID-19 vaccine prior to the appearance of symptoms. CONCLUSION: The findings highlight the diagnostic utility of advanced ocular imaging in detecting AMN in COVID-19 patients and the importance of comprehensive eye examinations.

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A catalyst-free mild synthesis was reported to produce medium-ring oxazepane and oxazocine derivatives from aminomaleimides and N-alkyl amines. The substrate and acidic additives were employed to cleave the C(sp3)-N bond as a one-carbon synthon for C-C and C-O coupling, thus facilitating the [n + 1] cascade cyclization reaction, which enabled the construction of seven- and eight-membered N,O-heterocycles at room temperature. The method exhibits abroad substrate scope and remarkable tolerance toward various functional groups (seven-membered 28 examples, eight-membered 8 examples, and activated N-alkyl amine 12 examples) and utilization of natural products (2 examples).

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Dechloranes are additive-type chlorine flame retardants that are widely used in processing industrial products, such as electronic equipment and textiles. Dechloranes, which can enter the human body through various routes, pose significant health risks because of their toxicity, persistence, and bioaccumulation. In 2023, dechlorane plus was listed in the Stockholm Convention on Persistent Organic Pollutants. In the same year, China recognized this compound as a priority-controlled substance. Dechloranes are commonly found at trace levels in water, which is extremely harmful to the environment and human health. Therefore, the development of detection methods for dechloranes is crucial. Magnetic solid-phase extraction (MSPE) has attracted considerable attention because of its low organic solvent consumption, simplicity of adsorbent separation, and ease of operation. In general, the selectivity and efficiency of MSPE depend on the characteristics of the adsorbent. Covalent organic frameworks (COFs) have regular porosity, structural predictability and stability, high specific surface areas, and adjustable pore sizes, which are advantageous for a wide range of separation and analysis applications. In this study, Fe3O4 magnetic nanoparticles and a COF material (TpBD) were combined to prepare Fe3O4@TpBD as an adsorbent for dechloranes. Subsequently, an effective method for analyzing dechlorane in environmental water was established by coupling MSPE with gas chromatography-negative chemical ionization mass spectrometry (GC-NCI/MS). The successful synthesis of Fe3O4@TpBD was confirmed using transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and vibrating sample magnetometry. A single-factor method was used to optimize the extraction conditions, including the Fe3O4@TpBD dosage, pH of water sample, elution solvent type and volume, extraction time, elution time, and ionic strength. The target analytes were separated on a TG-5SILMS column (30 m×0.25 mm×0.25 µm) and quantified using the external standard method in the selected-ion monitoring (SIM) mode. Under the optimal extraction conditions, the method validation results showed a linear range of 2-1000 ng/L. The limits of detection (LODs) and quantification (LOQs) were 0.18-0.27 ng/L and 0.60-0.92 ng/L, respectively, for the three analytes. The intra-day and inter-day precisions at three spiked levels were 4.2%-16.2% and 6.9%-15.7%, respectively. This method was successfully applied to the determination of dechloranes in environmental water samples (laboratory tap water, reservoir water, wastewater treatment plant effluent, and landfill leachate treatment effluent). The recoveries of the three dechloranes at different spiked levels ranged from 77.8% to 113.3% with relative standard deviations (RSDs) of 2.5%-16.3% (n=3). With the advantages of operational simplicity, high sensitivity, and good reproducibility, the proposed method is suitable for the qualitative and quantitative determination of dechloranes in environmental water.

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Integrating structural colors and conductivity into aqueous inks has the potential to revolutionize wearable electronics, providing flexibility, sustainability, and artistic appeal to electronic components. This study aims to introduce bioinspired color engineering to conductive aqueous inks. Our self-assembly approach involves mixing poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) with sulfonic acid-modified polystyrene (sPS) colloids to generate non-iridescent structural colors in the inks. This spontaneous structural coloration occurs because PEDOT:PSS and sPS colloids can self-assemble into core-shell structures and reversibly cluster into photonic aggregates of maximally random jammed packing within the aqueous environment, as demonstrated by small-angle X-ray scattering. Dissipative particle dynamics simulation confirms that the self-assembly aggregation of PEDOT:PSS chains and sPS colloids can be manipulated by the polymer-colloid interactions. Utilizing the finite-difference time-domain method, we demonstrate that the photonic aggregates of the core-shell colloids achieve close to maximum jammed packing, making them suitable for producing vivid structural colors. These versatile conductive inks offer adjustable color saturation and conductivity, with conductivity levels reaching 36 S cm-1 through the addition of polyethylene glycol oligomer, while enhanced water resistance and mechanical stability are achieved by doping with a cross-linker, poly(ethylene glycol) diglycidyl ether. With these unique features, the inks can create flexible, patterned circuits through processes like coating, writing, and dyeing on large areas, providing eco-friendly, visually appealing colors for customizable, stylish, comfortable, and wearable electronic devices.

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Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder associated with abnormally elevated neuroinflammatory responses. Suppression of neuroinflammation is considered to be effective in ameliorating PTSD-like behaviors in rodents. Since pre-stimulation of microglia prior to stress exposure can prevent neuroinflammation, we hypothesized that pre-stimulation of microglia may prevent PTSD in animals. The results show that a single injection of a classical immune stimulant, lipopolysaccharide (LPS), at 50, 100 or 500, but not 10 µg/kg, one day before stress exposure, prevented the anxiety- and fear-like behaviors induced by modified single prolonged stress (mSPS). The time-dependent analysis shows that a single injection of LPS (100 µg/kg) either one or five, but not ten, days before stress prevented mSPS-induced anxiety- and fear-like behaviors. A second low-dose LPS injection 10 days after the first injection or a repeated LPS injection (4 × ) 10 days before stress induced tolerance to mSPS. Mechanistic studies show that a single injection of LPS one day before stress stimulation prevented mSPS-induced increases in levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of microglia by pretreatment with minocycline or depletion of microglia by PLX3397 abolished the preventive effect of low-dose LPS pre-injection on mSPS-induced anxiety- and fear-like behavior and neuroinflammatory responses. These results suggest that pre-stimulation of microglia may prevent the development of PTSD-like behaviors by attenuating the development of neuroinflammatory responses. This could help to develop new strategies to prevent the damaging effects of harmful stress on the brain.

Assuntos

Ansiedade , Medo , Lipopolissacarídeos , Microglia , Doenças Neuroinflamatórias , Transtornos de Estresse Pós-Traumáticos , Animais , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/imunologia , Camundongos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Ansiedade/imunologia , Ansiedade/metabolismo , Doenças Neuroinflamatórias/imunologia , Imunização/métodos , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Comportamento Animal/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Camundongos Endogâmicos C57BL , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/imunologia

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BACKGROUND: Disulfidptosis is a newly identified mechanism of cell death triggered by disulfide stress. Thus, gaining a comprehensive understanding of the disulfidptosis signature present in gastric cancer (GC) could greatly enhance the development of personalized treatment strategies for this disease. METHODS: We employed consensus clustering to identify various subtypes of disulfidptosis and examined the distinct tumor microenvironment (TME) associated with each subtype. The Disulfidptosis (Dis) score was used to quantify the subtype of disulfidptosis in each patient. Subsequently, we assessed the predictive value of Dis score in terms of GC prognosis and immune efficacy. Finally, we conducted in vitro experiments to explore the impact of Collagen X (COL10A1) on the progression of GC. RESULTS: Two disulfidptosis-associated molecular subtypes (Discluster A and B) were identified, each with distinct prognosis, tumor microenvironment (TME), immune cell infiltration, and biological pathways. Discluster A, characterized by high expression of disulfidptosis genes, exhibited a high immune score but poor prognosis. Furthermore, the Dis score proved useful in predicting the prognosis and immune response in GC patients. Those in the low Dis score group showed better prognosis and increased sensitivity to immunotherapy. Finally, our experimental findings validated that downregulation of COL10A1 expression attenuates the proliferation and migration capabilities of GC cells while promoting apoptosis. CONCLUSIONS: This study demonstrates that the disulfidptosis signature can assist in risk stratification and personalized treatment for patients with GC. The results offer valuable theoretical support for anti-tumor strategies.

Assuntos

Neoplasias Gástricas , Microambiente Tumoral , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Humanos , Microambiente Tumoral/imunologia , Prognóstico , Linhagem Celular Tumoral , Apoptose