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Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.
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Células Madre Mesenquimatosas , MicroARNs , Infarto del Miocardio , Nanopartículas , Infarto del Miocardio/terapia , Animales , Nanopartículas/química , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , MicroARNs/metabolismo , MicroARNs/genética , Masculino , Recuperación de la Función , Trasplante de Células Madre Mesenquimatosas/métodos , Humanos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Ratones , Microburbujas , Ondas UltrasónicasRESUMEN
Purpose: Currently, there is still no clear treatment for polycystic ovary syndrome (PCOS). YJKL has better therapeutic effects and lower toxic side effects for PCOS type infertility. This study aims to clarify the potential mechanism of YJKL Decoction in the treatment of PCOS based on network pharmacology and experiments verification. Patients and Methods: Network pharmacology and experimental validation approach were used to investigate the bioactive ingredients, critical targets and potential mechanisms of YJKL Decoction against PCOS. Firstly, we use network pharmacology methods to collect core targets, and then validate their effects on diseases through experiments. Results: Five core targets were screened, Threonine kinase 1 (AKT1), Cellular tumor antigen p53 (TP53), Tumor necrosis factor (TNF), Albumin (ALB) and Vascular endothelial growthfactor A (VEGFA). KEGG analysis showed that YJKL treatment for PCOS mainly include AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway and HIF-1 signaling pathway. The molecular docking results showed that compounds have higher affinity with targets. Finally, experimental results had shown that YJKL Decoction had an better therapeutic effects in the treatment of PCOS. Conclusion: Based on a systematic network pharmacology approach and experimental verification, our results comprehensively illustrated the active ingredients, potential targets, and molecular mechanism of YJKL for application to PCOS and helps to illustrate mechanism of action on a comprehensive level.
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Medicamentos Herbarios Chinos , Farmacología en Red , Síndrome del Ovario Poliquístico , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Simulación del Acoplamiento Molecular , Animales , Infertilidad Femenina/tratamiento farmacológicoRESUMEN
Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural-specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high-fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity-induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD-induced obesity and associated depression. Thus, a WFS1-ZnT3-Zn2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.
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Psychrophilic bacteria, the dominant spoilage organisms in raw milk, secrete heat-stable extracellular proteases and lipases that lead to the decomposition of milk and dairy products. In this study, we investigated psychrophilic bacteria in 165 raw milk samples collected across four seasons and six regions in China using shotgun metagenomic sequencing and traditional culture methods. The isolated psychrophilic bacteria were classified into 40 genera and 185 species. Pseudomonas was the most prevalent, accounting for 51.13 % of the genera, while Lactococcus and Chryseobacterium were also notably abundant (> 6.0 %). Metagenomic sequencing revealed that Pseudomonas (47.9 %), Stenotrophomonas (9.75 %), Sphingomonas (6.73 %), Latilactobacillus (6.38 %) and Lactococcus (5.16 %) were the dominant genera in the raw milk samples. The diversity of psychrophilic bacteria in raw milk was strongly influenced by seasonal variations, with the sampling region being a less significant factor. KEGG annotation indicated that carbohydrate and amino acid metabolism were the primary metabolic pathways in these bacteria. Metagenomic sequencing not only accurately identifies species but also provides functional insights into psychrophilic bacteria in raw milk, aiding in understanding their activities, promoting their control on farms, and ultimately improving raw milk quality.
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BACKGROUND: The use of proteasome inhibitors (PIs), namely Bortezomib and Carfilzomib, revolutionized multiple myeloma (MM) treatment. Understanding their distinct adverse event (AE) profiles aids in tailored treatment plans. RESEARCH DESIGN AND METHODS: We analyzed FDA Adverse Event Reporting System (FAERS) data (Q1 2012-Q4 2023) for Bortezomib and Carfilzomib, utilizing reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN). RESULTS: FAERS yielded 19,720 Bortezomib and 12,252 Carfilzomib AE reports. Males aged 45-65 exhibited higher AE susceptibility. Common AE systems included Infections, Nervous System Disorders, Blood Disorders, General Disorders, Cardiac Disorders, and Renal Disorders. New Bortezomib signals were sepsis and colitis. Carfilzomib exhibited elevated cardiac and renal toxicity but reduced peripheral neuropathy and thrombocytopenia. CONCLUSIONS: FAERS analysis revealed new AE signals (sepsis, colitis) for Bortezomib and highlighted Carfilzomib's heightened cardiac and renal risks compared to Bortezomib. Balancing PIs' benefits and risks is crucial for clinical decision-making.
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Cd ions are absorbed and transported from the soil by crop roots, which are the first organ to be exposed to Cd. This results in an increase in cadmium ions in crops, significantly affecting crop growth and yield. Exogenous melatonin (MT) can help reduce cadmium (Cd) stress in cotton, but the specific contribution of roots to this process remains unclear. In order to address this knowledge gap, an in-situ root phenotyping study was conducted to investigate the the phenotype and lifespan of roots under cadmium stress (Cd) and melatonin treatment (Cd + MT). The results showed that MT alleviated the decreases in plant height, leaf area, SPAD value, stem diameter, stomatal conductance and net photosynthetic rate under Cd stress, which further promoted the biomass accumulation in various cotton organs. What is more, the Cd + MT treatment increased root volume, surface area, and length under Cd stress by 25.63â¯%, 10.58â¯%, and 21.89â¯%, respectively, compared with Cd treatment. Interestingly, compared to Cd treatment, Cd + MT treatment also significantly extended the lifespan of roots and root hairs by 6.68 days and 2.18 days, respectively. In addition, Cd + MT treatment reduced the transport of Cd from roots to shoots, particularly to bolls, and decreased the Cd bioconcentration factor in bolls by 61.17â¯%, compared to Cd treatment. In conclusion, these findings show that applying MT externally helps reduce Cd stress by delaying root senescence, promoting root development and regulating Cd transport. This method can be an effective approach to managing Cd stress in cotton.
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Cadmio , Gossypium , Melatonina , Raíces de Plantas , Contaminantes del Suelo , Gossypium/efectos de los fármacos , Gossypium/crecimiento & desarrollo , Melatonina/farmacología , Cadmio/toxicidad , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/crecimiento & desarrollo , Contaminantes del Suelo/toxicidad , Transporte Biológico/efectos de los fármacosRESUMEN
BACKGROUND: However, the connection between smoking and the prognosis of patients with bladder cancer remains unclear. AIM: To determine whether smoking is linked to the recurrence and progression of bladder cancer. METHODS: As of July 20, 2022, relevant English-language research was identified by searching PubMed, the Web of Science, and the Cochrane Library. We pooled the available data from the included studies using a random effects model. Subgroup analysis and sensitivity analysis were also conducted. RESULTS: A total of 12 studies were included in this meta-analysis. The combined analysis revealed that tobacco exposure was associated with a significantly greater recurrence rate than nonsmoking status [odd ratios (OR) = 1.76, 95%CI: 1.84-2.93], and the progression of bladder cancer was significantly greater in smokers than in nonsmokers (OR = 1.21, 95%CI: 1.02-1.44). Stratified analysis further revealed that current smokers were more likely to experience relapse than never-smokers were (OR = 1.85, 95%CI: 1.11-3.07). Former smokers also had a greater risk of relapse than did never-smokers (OR = 1.73, 95%CI: 1.09-2.73). Subgroup analysis indicated that non-Caucasians may be more susceptible to bladder cancer recurrence than Caucasians are (OR = 2.13, 95%CI: 1.74-2.61). CONCLUSION: This meta-analysis revealed that tobacco exposure may be a significant risk factor for both the recurrence and progression of bladder cancer.
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INTRODUCTION: The antidepressant properties of Hypericum species are known. Hyperibone J, a principal component found in the flowers of Hypericum bellum, exhibited in vitro anti-inflammatory effects. However, the antidepressant effects and mechanisms of Hyperibone J remain to be elucidated. Adenosine kinase (ADK) is upregulated in epilepsy and depression and has been implicated in promoting neuroinflammation. OBJECTIVES: This study aimed to explore the impact of Hyperibone J on neuroinflammation-mediated depression and the mechanism underlying this impact. METHODS: This study employed acute and chronic in vivo depression models and an in vitro LPS-induced depression model using BV-2 microglia. The in vivo antidepressant efficacy of Hyperibone J was assessed through behavioral assays. Techniques such as RNA-seq, western blot, qPCR and ELISA were utilized to elucidate the direct target and mechanism of action of Hyperibone J. RESULTS: Compared with the model group, depression-like behaviors were significantly alleviated in the Hyperibone J group. Furthermore, Hyperibone J mitigated hippocampal neuroinflammation and neuronal damage. RNA-seq suggested that Hyperibone J predominantly influenced inflammation-related pathways. In vitro experiments revealed that Hyperibone J reversed the LPS-induced overexpression and release of inflammatory factors. Network pharmacology and various molecular biology experiments revealed that the potential binding of Hyperibone J at the ASN-312 site of ADK diminished the stability and protein expression of ADK. Mechanistic studies revealed that Hyperibone J attenuated the ADK/ATP/P2X7R/Caspase-1-mediated maturation and release of IL-1ß. The study also revealed a significant correlation between Tlr4 expression and depression-like behaviors in mice. Hyperibone J downregulated ADK, inhibiting Tlr4 transcription, which in turn reduced the phosphorylation of NF-κB and the subsequent transcription of Nlrp3, Il-1b, Tnf, and Il-6. CONCLUSION: Hyperibone J exerted antineuroinflammatory and antidepressant effects by binding to ADK in microglia, reducing its expression and thereby inhibiting the ATP/P2X7R/Caspase-1 and TLR4/NF-κB pathways. This study provides experimental evidence for the therapeutic potential of Hypericum bellum.
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Abrus cantoniensis Hance is a vegetative food and can be used as a folk beverage or soup to clear liver toxins and prevent liver damage. However, the components and effects of A. cantoniensis Hance in alcohol-induced liver injury were unknown. This study aimed to obtain abundant phytochemicals from A. cantoniensis Hance and identify the potency of the isolates in preventing alcohol-induced liver injury. Alcohol-stimulated AML12 cells and Lieber-DeCarli diet-fed mice were used to establish in vitro and in vivo models, respectively. Our findings indicated that flavonoid glycosides, especially AH-15, could significantly alleviate alcohol-induced liver injury by inhibiting oxidative stress. Furthermore, we demonstrated that AH-15 inhibited ferroptosis induced by lipid peroxidation. Mechanically, we found that AH-15 regulated nuclear factor erythroid 2-related factor 2 (NRF2) expression via activation of AMP-activated protein kinase (AMPK) signaling. These results indicate that A. cantoniensis Hance is a great potential functional food for alleviating alcohol-induced liver injury.
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Proteínas Quinasas Activadas por AMP , Abrus , Ferroptosis , Flavonoides , Glicósidos , Hepatopatías Alcohólicas , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Extractos Vegetales , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Ratones , Glicósidos/farmacología , Glicósidos/química , Ferroptosis/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/química , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Extractos Vegetales/farmacología , Extractos Vegetales/química , Humanos , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/prevención & control , Abrus/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Estrés Oxidativo/efectos de los fármacos , Línea CelularRESUMEN
Osteosarcoma, a prevalent primary malignant bone tumor, often presents with lung metastases, severely impacting patient survival rates. Extracellular vesicles, particularly exosomes, play a pivotal role in the formation and progression of osteosarcoma-related pulmonary lesions. However, the communication between primary osteosarcoma and exosome-mediated pulmonary lesions remains obscure, with the potential impact of pulmonary metastatic foci on osteosarcoma progression largely unknown. This study unveils an innovative mechanism by which exosomes originating from osteosarcoma pulmonary metastatic sites transport the miR-194/215 cluster to the primary tumor site. This transportation enhances lung metastatic capability by downregulating myristoylated alanine-rich C-kinase substrate (MARCKS) expression. Addressing this phenomenon, in this study we employ cationic bovine serum albumin (CBSA) to form nanoparticles (CBSA-anta-194/215) via electrostatic interaction with antagomir-miR-194/215. These nanoparticles are loaded into nucleic acid-depleted exosomal membrane vesicles (anta-194/215@Exo) targeting osteosarcoma lung metastatic sites. Intervention with bioengineered exosome mimetics (anta-194/215@Exo) not only impedes osteosarcoma progression but also significantly prolongs the lifespan of tumor-bearing mice. These findings suggest that pulmonary metastatic foci-derived exosomes initiate primary osteosarcoma lung metastasis by transferring the miR-194/215 cluster targeting MARCKS, making the miR-194/215 cluster a promising therapeutic target for inhibiting the progression of patients with osteosarcoma lung metastases.
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Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.
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Hypericum , Monoterpenos , Floroglucinol , Fitoquímicos , Hypericum/química , Ratones , Estructura Molecular , Monoterpenos/aislamiento & purificación , Monoterpenos/farmacología , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Floroglucinol/química , Células RAW 264.7 , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Animales , Óxido Nítrico/metabolismo , Estereoisomerismo , ChinaRESUMEN
Garciyunnanones A-R (1-18), eighteen undescribed caged polycyclic polyprenylated acylphloroglucinols, two undescribed biogenetic congeners (19-20), and nineteen known analogues (21-39), were isolated from the stem barks of Garcinia yunnanensis Hu. All of these isolates are decorated with a C-5 lavandulyl substituent. Their structures and absolute configurations were confirmed by HRESIMS, 1D & 2D NMR spectroscopic analysis, quantum chemical calculations of electronic circular dichroism data, and single-crystal X-ray diffraction analysis. The X-ray crystallographic data of ten isolated caged compounds ascertained the absolute configuration of C-23 in the lavandulyl as S. The cytotoxicity on three cancer cell lines and the anti-nonalcoholic steatohepatitis activity of the isolates were tested. In a free fatty acid-induced L02 cell model, compounds 33 and 39 decreased intracellular lipid accumulation significantly.
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Antineoplásicos Fitogénicos , Garcinia , Floroglucinol , Garcinia/química , Humanos , Floroglucinol/química , Floroglucinol/farmacología , Floroglucinol/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Modelos Moleculares , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Corteza de la Planta/químicaRESUMEN
Electrochemical C-H mono/multi-bromination regulation of N-sulfonylanilines on the cost-effective CF electrode is described. This reaction proceeds smoothly under mild conditions with a broad substrate scope, affording diverse mono/multi-brominated anilines in moderate to good yields. Mechanism study reveals that this transformation involves anodic oxidation, aromatic electrophilic substitution, and deprotonation. Preliminary electroactive molecule screening results in its prospective application in electroactive MBs for electrochemical biosensors.
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BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.
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Neovascularización Coroidal , Degeneración Macular , Miopía Degenerativa , Enfermedades de la Retina , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Factores de Crecimiento Endotelial/uso terapéutico , Miopía Degenerativa/complicaciones , Miopía Degenerativa/diagnóstico , Agudeza Visual , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/tratamiento farmacológico , Neovascularización Coroidal/etiología , Enfermedades de la Retina/diagnóstico , Degeneración Macular/tratamiento farmacológico , Esclerótica , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Angiografía con Fluoresceína , Inyecciones IntravítreasRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine Gegen Qinlian Decoction (GQD) has been clinically shown to be an effective treatment of ulcerative colitis (UC) in China. However, the underlying mechanism of GQD's anti-ulcerative colitis properties and its effect on gut microbiota still deserve further exploration. AIM OF THE STUDY: This study observed the regulatory effects of GQD on Th2/Th1 and Tregs/Th17 cells balance, the NOD-like receptor family pyrin domain containing 3 (NLRP3) infammasome and gut microbiota in TNBS-induced UC in BALB/c mice. MATERIALS AND METHODS: 61 main chemical compounds in the GQD were determined by UPLC-Q-TOF/MS. The UC BALB/c model was established by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and GQD was orally administered at low and high dosages of 2.96 and 11.83 g/kg/day, respectively. The anti-inflammatory effects of GQD for ulcerative colitis were evaluated by survival rate, body weight, disease activity index (DAI) score, colonic weight and index, spleen index, hematoxylin-eosin (HE) staining and histopathological scores. Flow cytometry was used to detect the percentage of CD4, Th1, Th2, Th17 and Tregs cells. The levels of Th1-/Th2-/Th17-/Tregs-related inflammatory cytokines and additional proinflammatory cytokines (IL-1ß, IL-18) were detected by CBA, ELISA, and RT-PCR. The expressions of GATA3, T-bet, NLRP3, Caspase-1, IL-Iß, Occludin and Zonula occludens-1 (ZO-1) on colon tissues were detected by Western blot and RT-PCR. Transcriptome sequencing was performed using colon tissue and 16S rRNA gene sequencing was performed on intestinal contents. Fecal microbiota transplantation (FMT) was employed to assess the contribution of intestinal microbiota and its correlation with CD4 T cells and the NLRP3 inflammasome. RESULTS: GQD increased the survival rate of TNBS-induced UC in BALB/c mice, and significantly improved their body weight, DAI score, colonic weight and index, spleen index, and histological characteristics. The intestinal barrier dysfunction was repaired after GQD administration through promoting the expression of tight junction proteins (Occludin and ZO-1). GQD restored the balance of Th2/Th1 and Tregs/Th17 cells immune response of colitis mice, primarily inhibiting the increase in Th2/Th1 ratio and their transcription factor production (GATA3 and T-bet). Morever, GQD changed the secretion of Th1-/Th2-/Th17-/Tregs-related cytokines (IL-2, IL-12, IL-5, IL-13, IL-6, IL-10, and IL-17A) and reduced the expressions of IL-1ß, IL-18. Transcriptome results suggested that GQD could also remodel the immune inflammatory response of colitis by inhibiting NOD-like receptor signaling pathway, and Western blot, immunohistochemistry and RT-PCR further revealed that GQD exerted anti-inflammatory effects by inhibiting the NLRP3 inflammasome, such as down-regulating the expression of NLRP3, Caspase-1 and IL-1ß. More interestingly, GQD regulated gut microbiota dysbiosis, suppressed the overgrowth of conditional pathogenic gut bacteria like Helicobacter, Proteobacteria, and Mucispirillum, while the probiotic gut microbiota, such as Lactobacillus, Muribaculaceae, Ruminiclostridium_6, Akkermansia, and Ruminococcaceae_unclassified were increased. We further confirmed that GQD-treated gut microbiota was sufficient to relieve TNBS-induced colitis by FMT, involving the modulation of Th2/Th1 and Tregs/Th17 balance, inhibition of NLRP3 inflammasome activation, and enhancement of colonic barrier function. CONCLUSIONS: GQD might alleviate TNBS-induced UC via regulating Th2/Th1 and Tregs/Th17 cells Balance, inhibiting NLRP3 inflammasome and reshaping gut microbiota, which may provide a novel strategy for patients with colitis.
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Colitis Ulcerosa , Colitis , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Humanos , Ratones , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Medicamentos Herbarios Chinos/efectos adversos , Inflamasomas/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacología , Interleucina-18/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Th17 , Ocludina/metabolismo , ARN Ribosómico 16S/metabolismo , Ratones Endogámicos CBA , Colitis/tratamiento farmacológico , Citocinas/metabolismo , Trinitrobencenos/metabolismo , Trinitrobencenos/farmacología , Trinitrobencenos/uso terapéutico , Antiinflamatorios/farmacología , Peso Corporal , Caspasas/metabolismo , Modelos Animales de Enfermedad , ColonRESUMEN
To address the issue of ineffective injection resulting from the consistent channeling of injected water through highly permeable channels in ultra-deep, high-temperature, high-salinity, and strongly heterogeneous reservoirs during the production process, a gel particle profile control agent suitable for high-temperature and high-salinity conditions was chosen. With the help of the glass etching visual microscopic model and the heterogeneous long core model, the formation mechanism of a water flooding channeling path and the distribution law of the remaining oil were explored, the microscopic profile control mechanism of the different parameters was clarified, and the profile control effect of macroscopic core displacement was analyzed. The research shows that the formation mechanism of a water flooding channeling path is dominated by the distribution law of the permeability section and the connection mode between different penetration zones. The remaining oil types after water flooding are mainly contiguous block, parallel throats, and multi-branch clusters. The profile control effect of gel particles on reservoir vertical heterogeneity is better than that of reservoir lateral heterogeneity. It was found that 10 wt% submicron particles with a median diameter of 600 nm play a good role in profiling and plugging pores of 5-20 µm. In addition, 10 wt% micron-sized particles with a median diameter of 2.63 µm mainly play a strong plugging role in the pores of 20-30 µm, and 5 wt% micron-sized particles with a median diameter of 2.63 µm mainly form a weak plugging effect on the pores of 10-20 µm. The overall profile control effect of 10 wt% submicro particles is the best, and changes in concentration parameters have a more significant effect on the profile control effect. In the macroscopic core profile control, enhanced oil recovery (EOR) can reach 16%, and the gel particles show plugging, deformation migration, and re-plugging. The research results provide theoretical guidance for tapping the potential of the remaining oil in strong heterogeneous reservoirs. To date, the gel particles have been applied in the Tahe oilfield and have produced an obvious profile control effect; the oil production has risen to the highest value of 26.4 t/d, and the comprehensive water content has fallen to the lowest percentage of 32.1%.
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Disulfidptosis, a newly revealed form of cell death, regulated by numerous genes that has been recently identified. The exact role of disulfidptosis in lung adenocarcinoma (LUAD) still uncertain. Objective of this study was to explore potential prognostic markers among disulfidptosis genes in LUAD. By combining transcriptomic information from Gene Expression Omnibus databases and The Cancer Genome Atlas, we identified differentially expressed and prognostic disulfidptosis genes. By conducting least absolute shrinkage and selection operator with multivariate Cox regression, four disulfidptosis genes were selected to create the prognostic signature. The implementation of the signature separated the training and validation cohorts into groups with high- and low-risk. Subsequently, the model was verified by conducting an independent analysis of receiver operating characteristic (ROC) curves. Further comparisons were made between the two risk-divided groups with regards the tumor microenvironment, immune cell infiltration, immunotherapy response, and drug sensitivity. The signature was constructed using four disulfidptosis-related genes: SLC7A11, SLC3A2, NCKAP1, and GYS1. According to ROC curves, the signature was effective for predicting LUAD prognosis. In addition, the prognostic signature correlated with sensitivity to chemotherapeutic agents and the efficacy of immunotherapy in LUAD. Finally, through external validation, we showed that NCKAP1 are correlated with tumor migration, proliferation, and invasion of LUAD cells. GYS1 affects immune cell, especially M2 macrophage infiltration in the tumor microenvironment. The disulfidptosis four-gene model can reliably predict the prognosis of patients diagnosed with LUAD, thereby providing valuable information for clinical applications and immunotherapy.
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Sensing materials innovation plays a crucial role in the development of high-performance film-based fluorescent sensors (FFSs). In our current study, we present the innovative fabrication of four fluorescent nanofilms via interfacially confined dynamic reaction of a specially designed fluorescent building block, a new boron-coordinated compound (NI-CHO), with a chosen one, benzene-1,3,5-tricarbohydrazide (BTH). The nanofilms as prepared are robust, uniform, flexible, and thickness tunable, at least from 40 to 1500 nm. The fabricated FFSs based on Film 3, one of the four nanofilms, shows highly selective and fully reversible response to NH3 vapor with an experimental detection limit of <0.1 ppm and a response time of 0.2 s. The unprecedented high performance of the nanofilm is ascribed to the specific quenching of its fluorescence emission owing to formation of an excited-state complex between the sensing unit and the analyte molecule. Efficient mass transfer also contributes to the high performance owing to the porous adlayer structure of the nanofilm. This work provides an example to show how to develop a high-performance sensing film via controlling the film's structure, especially the thickness.
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Searching for new anti-ischemic stroke (anti-IS) drugs has always been a hot topic in the pharmaceutical industry. Natural products are an important source of discovering anti-IS drugs. The aim of the present study is to extract, rapidly prepare and explore the neuroprotective effect of texasin, a main active constituent from Caragana jubata (Pall.) Poir., which is a kind of Tibetan medicine with a clear anti-IS effect. The results showed that 95% ethanol was the optimal extraction solvent. A three-step rapid preparation method for texasin was successfully established, with a purity of 99.2%. Texasin at the concentration of 25-100 µM had no effect on the viability of normal cultured PC12 cells; 12.5 and 25 µM texasin could enhance the viability of PC12 cells damaged by oxygen and glucose deprivation/reoxygenation (OGD/R), and their effects are comparable to the positive drug edaravone at the concentration of 50 µM. Compared with the normal group, the expression of Bcl-2 protein in OGD/R-injured PC12 cells was downregulated (p < 0.01), and that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins were upregulated (p < 0.01, p < 0.001). Compared with the OGD/R group, 25 µM texasin could upregulate the expression of Bcl-2 protein (p < 0.01), and downregulate that of PERK, eIF2α, ATF4, CHOP, Bax and Cleaved caspase-3 proteins (p < 0.01, p < 0.001). The 7-OH and 1-O of texasin formed H-bonds with residues Cys891 of the hinge ß-strand of PERK, which is crucial for kinase inhibitors. The above results suggest that the method established in the present study achieved rapid preparation of high-purity texasin. Texasin might inhibit neuronal apoptosis via the regulation of endoplasmic reticulum stress PERK/eIF2α/ATF4/CHOP signalling pathway to exert a protective effect on OGD/R-injured PC12 cells. Aiding by molecular docking, texasin was assumed to be a potential PERK inhibitor.
RESUMEN
Transition state (TS) on the potential energy surface (PES) plays a key role in determining the kinetics and thermodynamics of chemical reactions. Inspired by the fact that the dynamics of complex systems are always driven by rare but significant transition events, we herein propose a TS search method in accordance with the Q-learning algorithm. Appropriate reward functions are set for a given PES to optimize the reaction pathway through continuous trial and error, and then the TS can be obtained from the optimized reaction pathway. The validity of this Q-learning method with reasonable settings of Q-value table including actions, states, learning rate, greedy rate, discount rate, and so on, is exemplified in 2 two-dimensional potential functions. In the applications of the Q-learning method to two chemical reactions, it is demonstrated that the Q-learning method can predict consistent TS and reaction pathway with those by ab initio calculations. Notably, the PES must be well prepared before using the Q-learning method, and a coarse-to-fine PES scanning scheme is thus introduced to save the computational time while maintaining the accuracy of the Q-learning prediction. This work offers a simple and reliable Q-learning method to search for all possible TS and reaction pathway of a chemical reaction, which may be a new option for effectively exploring the PES in an extensive search manner.