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In this study, the full-length cDNA sequences of the phosphatidylinositol-3-kinase p85 alpha (PI3KR1) and serine/threonine kinase 1 (AKT1) genes in largemouth bass (Micropterus salmoides) were obtained using the rapid amplification of cDNA ends (RACE) method. Sequence analysis revealed that the cloned sequences of PI3KR1 and AKT1 are 4170 bp and 3672 bp in length, with open reading frames (ORFs) of 1389 bp and 1422 bp encoding 462 and 473 amino acids, respectively. Sequence alignment and evolutionary tree analysis indicated their close relationship to other teleosts, especially those with similar feeding habits. Tissue distribution demonstrated widespread distribution of both genes in various tissues, with the highest abundance in the liver. Further results found that the upregulation of the expression of p-PI3KR1, p-AKT1, p-FoxO1, and GLUT2 proteins by insulin, while suppressing the expression of the total FoxO1 protein, effectively triggers a significant activation of the PI3KR1-AKT1 insulin signaling pathway. Meanwhile, the mRNA levels of the key glycolytic genes, including glucokinase (gk), pyruvate kinase (pk), and phosphofructokinase liver type (pfkl), have been enhanced evidently. In contrast, the expression of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (pepck), glucose-6-phosphatase catalytic subunit (g6pc), and fructose-1,6-bisphosphatase-1 (fbp1) has been notably down-regulated. In addition, insulin treatment promoted the phosphorylation of glycogen phosphorylase (PYGL) and the dephosphorylation of glycogen synthase (GS), and the glycogen content in the insulin-treated group was remarkably reduced compared to the control group. Overall, our study indicates that the activation of PI3KR1-AKT1 insulin signaling pathway represses the hepatic glycogen deposition via the regulation of glycolysis and gluconeogenesis, which provides some new insights into nutritional strategy to effectively regulate the glucose metabolism in carnivorous fish.
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Pot experiments were conducted using Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) and Phoebe bournei (Hemsl.) Yang) to investigate whether soil microplastics adversely affect the nurturing and renewal of plantations. Microplastics composed of polyethylene and polypropylene with a size of 48 µm were used. The treatments included a control group (without microplastics) and groups treated with microplastic concentrations of 1% and 2% (w/w). The effects of microplastics on the growth, photosynthetic pigments in leaves, antioxidant systems, and osmotic regulation substances of the seedlings were analysed by measuring the seedling height, ground-line diameter growth, chlorophyll (chlorophyll a, chlorophyll b, and total chlorophyll) contents, antioxidant enzyme (superoxide dismutase, peroxidase, catalase) activities, and malondialdehyde, soluble sugar, and soluble protein levels. The results indicated that treatment with 1% polyethylene microplastics increased the chlorophyll a, total chlorophyll, and soluble protein contents in the leaves of both types of seedlings while inhibiting superoxide dismutase and peroxidase activities in P. bournei seedlings. Treatment with 2% polyethylene or polypropylene microplastics suppressed the chlorophyll a, chlorophyll b, and total chlorophyll contents; superoxide dismutase, peroxidase, and catalase activities; and soluble sugar and soluble protein levels in the leaves of both types of seedlings, resulting in reduced growth in terms of height and ground-line diameter. The physiological effects of polyethylene microplastics were more evident than those of polypropylene at the same concentration. The results demonstrated that microplastics can affect photosynthesis, the antioxidant system, and osmotic regulation in Chinese fir and P. bournei seedlings, thereby inhibiting their normal growth and development. Exposure to 1% (w/w) microplastics triggered stress responses in seedlings, whereas 2% (w/w) microplastics impeded seedling growth.
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Clorofila , Microplásticos , Plantones , Contaminantes del Suelo , Superóxido Dismutasa , Contaminantes del Suelo/toxicidad , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Plantones/metabolismo , Clorofila/metabolismo , Superóxido Dismutasa/metabolismo , Microplásticos/toxicidad , Cunninghamia/efectos de los fármacos , Cunninghamia/crecimiento & desarrollo , Cunninghamia/metabolismo , Suelo/química , Catalasa/metabolismo , Clorofila A/metabolismo , Fotosíntesis/efectos de los fármacos , Peroxidasa/metabolismo , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/crecimiento & desarrollo , Malondialdehído/metabolismoAsunto(s)
Heparina , Rivaroxabán , Tromboelastografía , Humanos , Rivaroxabán/uso terapéutico , Heparina/uso terapéutico , Resistencia a Medicamentos , Trombosis/etiología , Trombosis/tratamiento farmacológico , Inhibidores del Factor Xa/uso terapéutico , Masculino , Femenino , Anticoagulantes/uso terapéutico , Anciano , Persona de Mediana EdadRESUMEN
PURPOSE: Recently, there has been rapid development in model-informed drug development, which has the potential to reduce animal experiments and accelerate drug discovery. Physiologically based pharmacokinetic (PBPK) and machine learning (ML) models are commonly used in early drug discovery to predict drug properties. However, basic PBPK models require a large number of molecule-specific inputs from in vitro experiments, which hinders the efficiency and accuracy of these models. To address this issue, this paper introduces a new computational platform that combines ML and PBPK models. The platform predicts molecule PK profiles with high accuracy and without the need for experimental data. METHODS: This study developed a whole-body PBPK model and ML models of plasma protein fraction unbound ( f up ), Caco-2 cell permeability, and total plasma clearance to predict the PK of small molecules after intravenous administration. Pharmacokinetic profiles were simulated using a "bottom-up" PBPK modeling approach with ML inputs. Additionally, 40 compounds were used to evaluate the platform's accuracy. RESULTS: Results showed that the ML-PBPK model predicted the area under the concentration-time curve (AUC) with 65.0 % accuracy within a 2-fold range, which was higher than using in vitro inputs with 47.5 % accuracy. CONCLUSION: The ML-PBPK model platform provides high accuracy in prediction and reduces the number of experiments and time required compared to traditional PBPK approaches. The platform successfully predicts human PK parameters without in vitro and in vivo experiments and can potentially guide early drug discovery and development.
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Aprendizaje Automático , Modelos Biológicos , Humanos , Células CACO-2 , Simulación por Computador , Farmacocinética , Descubrimiento de Drogas/métodos , Área Bajo la Curva , Administración Intravenosa , Masculino , Preparaciones Farmacéuticas/metabolismo , Proteínas Sanguíneas/metabolismoRESUMEN
PURPOSE: This scoping review aimed to understand the advances in radiomics in esophagogastric junction (EGJ) cancer and assess the current status of radiomics in EGJ cancer. METHODS: We conducted systematic searches of PubMed, Embase, and Web of Science databases from January 18, 2012, to January 15, 2023, to identify radiomics articles related to EGJ cancer. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies using the Radiomics Quality Score (RQS) and the METhodological RadiomICs Score (METRICS) tool, respectively. RESULTS: A total of 120 articles were retrieved from the three databases, and after screening, only six papers met the inclusion criteria. These studies investigated the role of radiomics in differentiating adenocarcinoma from squamous carcinoma, diagnosing T-stage, evaluating HER2 overexpression, predicting response to neoadjuvant therapy, and prognosis in EGJ cancer. The median score percentage of RQS was 34.7% (range from 22.2% to 38.9%). The median score percentage of METRICS was 71.2% (range from 58.2% to 84.9%). CONCLUSION: Although there is a considerable difference between the RQS and METRICS scores of the included literature, we believe that the research value of radiomics in EGJ cancer has been revealed. In the future, while actively exploring more diagnostic, prognostic, and biological correlation studies in EGJ cancer, greater emphasis should be placed on the standardization and clinical application of radiomics.
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Neoplasias Esofágicas , Unión Esofagogástrica , Neoplasias Gástricas , Humanos , Unión Esofagogástrica/diagnóstico por imagen , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Gástricas/diagnóstico por imagen , Pronóstico , RadiómicaRESUMEN
The design of efficient, stable and cost-effective electrocatalysts for the hydrogen evolution reaction holds substantial significance in water electrolysis, but it remains challenging. Tremella-like nickel-molybdenum bimetal phosphide encapsulated cobalt phosphide (NiMoP/CoP) with hierarchical architectures has been effectively synthesized on nickel foam (NF) via a straightforward hydrothermal followed by low-temperature phosphating method. Based on the unique structural benefits, it significantly increases the number of redox active centers, enhances the electrical conductivity of materials, and diminishes the ion diffusion path lengths, thereby promoting efficient electrolyte penetration and reducing the inherent resistance. The as-obtained NiMoP/CoP/NF electrocatalyst exhibited remarkable catalytic activity with an ultralow overpotential of 38 mV (10 mA cm-2) and low Tafel slope of 83 mV dec-1. The straightforward synthesis process and exceptional electrocatalytic properties of NiMoP/CoP/NF demonstrate great potential for the HER to replace the precious metal catalyst.
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This study aims to investigate the regulatory effects of Shenling Baizhu Powder(SBP) on cellular autophagy in alcoholic liver disease(ALD) and its intervention effect through the TLR4/NLRP3 pathway. A rat model of chronic ALD was established by gavage of spirits. An ALD cell model was established by stimulating BRL3A cells with alcohol. High-performance liquid chromatography(HPLC) was utilized for the compositional analysis of SBP. Liver tissue from ALD rats underwent hematoxylin-eosin(HE) and oil red O staining for pathological evaluation. Enzyme-linked immunosorbent assay(ELISA) was applied to quantify lipopolysaccharides(LPS), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-18(IL-18) levels. Quantitative reverse transcription polymerase chain reaction(qRT-PCR) was conducted to evaluate the mRNA expression of myeloid differentiation factor 88(MyD88) and Toll-like receptor 4(TLR4). The effect of different drugs on BRL3A cell proliferation activity was assessed through CCK-8 analysis. Western blot analysis was performed to examine the protein expression of NOD-like receptor pyrin domain-containing 3(NLRP3), nuclear factor-kappa B P65(NF-κB P65), phosphorylated nuclear factor-kappa B P65(p-P65), caspase-1, P62, Beclin1, and microtubule-associated protein 1 light chain 3(LC3â ¡). The results showed that SBP effectively ameliorated hepatic lipid accumulation, reduced liver function, mitigated hepatic tissue inflammation, and reduced levels of LPS, TNF-α, IL-1ß, and IL-18. Moreover, SBP exhibited the capacity to modulate hepatic autophagy induced by prolonged alcohol intake through the TLR4/NLRP3 signaling pathway. This modulation resulted in decreased expression of LC3â ¡ and Beclin1, an elevation in P62 expression, and the promotion of autolysosome formation. These research findings imply that SBP can substantially enhance liver function and mitigate lipid irregularities in the context of chronic ALD. It achieves this by regulating excessive autophagic responses caused by prolonged spirit consumption, primarily through the inhibition of the TLR4/NLRP3 pathway.
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Medicamentos Herbarios Chinos , Hepatopatías Alcohólicas , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Interleucina-18 , Polvos , Lipopolisacáridos , Factor de Necrosis Tumoral alfa , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Beclina-1 , FN-kappa B/metabolismo , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/genéticaRESUMEN
Purpose: To identify the prevalence of exacerbation of pre-existing chronic pain after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and investigate the impact of exacerbated previous chronic pain on quality of life, sleep quality, anxiety and depression levels and risk factors associated with exacerbated chronic pain among elderly coronavirus disease of 2019 (COVID-19) survivors. Patients and Methods: In this cross-sectional study, elderly COVID-19 survivors with chronic pain residing in Continuing Care Retirement Community (CCRC) were recruited from April 2023 to June 2023. Eligible individuals were divided into exacerbation and non-exacerbation groups based on the patient-reported worsening symptoms of previous chronic pain after SARS-CoV-2 infection. Baseline information, COVID-19 symptoms, laboratory parameters, characteristics of exacerbated chronic pain, quality of life, anxiety and depression levels were systematically collected. Results: Ninety-five (95/441, 21.5%) older adults suffered from exacerbated chronic pain with a median numerical rating scale (NRS) score of 6 (4-7) on a median duration of 4.9 (4.3-5.6) months after SARS-CoV-2 infection. More participants were not vaccinated against COVID-19 (46.5%, 40/86 vs 26.1%, 86/330, P < 0.001) in exacerbation group. Exacerbation group exhibited poor quality of life (EQ5D index: 0.734 [0.536-0.862] vs 0.837 [0.716-0.942], P < 0.001), more severe anxiety (GAD-7: 2 [0-5] vs 0 [0-3], P < 0.001) and depression (PHQ-9: 4 [2-7] vs 2.5 [0-5], P < 0.001) than non-exacerbation group. Risk factors significantly associated with exacerbation of pre-existing chronic pain were neuropathic pain (aOR 4.81, 95% CI 1.73-13.32, P = 0.003), lymphocyte count (aOR 0.31, 95% CI 0.12-0.78, P = 0.013) and D-dimer levels (aOR 6.46, 95% CI 1.92-21.74, P = 0.003). Conclusion: Our study observed a prevalence of 21.5% exacerbation of pre-existing chronic pain after SARS-CoV-2 infection, with a consequence of poor quality of life, more severe anxiety and depression. Previous chronic neuropathic pain, lower lymphocyte count and higher D-dimer levels were risk factors associated with the development of exacerbated previous chronic pain.
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BACKGROUND: Tuberculosis (TB), predominantly caused by Mycobacterium tuberculosis (MTB) infection, remains a prominent global health challenge. Macrophages are the frontline defense against MTB, relying on autophagy for intracellular bacterial clearance. However, MTB can combat and evade autophagy, and it influences macrophage polarization, facilitating immune evasion and promoting infection. We previously found that heparin-binding hemagglutinin (HBHA) inhibits autophagy in A549 cells; however, its role in macrophage autophagy and polarization remains unclear. METHODS: Bacterial cultures, cell cultures, Western blotting, immunofluorescence, macrophage infection assays, siRNA knockdown, and enzyme-linked immunosorbent assay were used to investigate HBHA's impact on macrophages and its relevance in Mycobacterium infection. RESULTS: HBHA inhibited macrophage autophagy. Expression of recombinant HBHA in Mycobacterium smegmatis (rMS-HBHA) inhibited autophagy, promoting bacterial survival within macrophages. Conversely, HBHA knockout in the Mycobacterium bovis bacillus Calmette-Guérin (BCG) mutant (BCG-ΔHBHA) activated autophagy and reduced bacterial survival. Mechanistic investigations revealed that HBHA may inhibit macrophage autophagy through the Toll-like receptor 4-dependent PI3K-AKT-mTOR signaling pathway. Furthermore, HBHA induced macrophage M2 polarization. CONCLUSIONS: Mycobacterium may exploit HBHA to suppress the antimicrobial immune response in macrophages, facilitating intracellular survival and immune evasion through autophagy inhibition and M2 polarization induction. Our findings may help identify novel therapeutic targets and develop more effective treatments against MTB infection.
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Autofagia , Macrófagos , Mycobacterium tuberculosis , Receptor Toll-Like 4 , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/metabolismo , Mycobacterium tuberculosis/inmunología , Humanos , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/genética , Transducción de Señal , Animales , Mycobacterium smegmatis/inmunología , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/metabolismo , Tuberculosis/inmunología , Tuberculosis/microbiología , Lectinas/metabolismo , Lectinas/genética , Ratones , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Evasión Inmune , Mycobacterium bovis/inmunología , Células A549 , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Investigations concerning the LPXRFa system are rarely conducted in flatfish species. Here, we first identified and characterized lpxrfa and its cognate receptor lpxrfa-r genes in the Japanese flounder (Paralichthys olivaceus). The coding DNA sequence of lpxrfa was 579 bp in length, wich encoded a 192-aa preprohormone that can produce three mature LPXRFa peptides. The open reading frame (ORF) of lpxrfa-r was 1446 bp in size, and encoded a 481-aa LPXRFa-R protein that encompassed seven hydrophobic transmembrane domains. Subsequently, tissue distribution expression profiles of lpxrfa and lpxrfa-r transcripts were assayed by quantitative real-time PCR. The results indicated that expressions of lpxrfa transcripts were detected at the highest levels in the brain of both females and males, however, lpxrfa-r transcripts were remarkablely expressed in the brain tissue of female fish and in the testis tissue of male fish. Furthermore, transcript levels of lpxrfa and lpxrfa-r genes were investigated during early ontogenetic development, with the maximum expression levels at 30 days post-hatching. Overall, these data contribute to providing preliminary proof for the existence and structure of the LPXRFa system in Japanese flounder, and the study is just the foundation for researching physiological function of LPXRFa system in this species.
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Lenguado , Péptidos , Animales , Femenino , Masculino , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Peces/genética , Lenguado/metabolismo , Péptidos/metabolismo , FilogeniaRESUMEN
Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in the treatment of CRC. In the present study, we designed a series of small-molecule Thiazole-based HDACis, among which HR488B bound to HDAC1 with a high affinity and exerted effective anti-CRC activity both in vitro and in vivo. Moreover, we revealed that HR488B specifically suppressed the growth of CRC cells by inducing cell cycle G0/G1 arrest and apoptosis via causing mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage accumulation. Importantly, we noticed that HR488B significantly decreased the expression of the E2F transcription factor 1 (E2F1), which was crucial for the inhibitory effect of HR488B on CRC. Mechanistically, HR488B obviously decreased the phosphorylation level of the retinoblastoma protein (Rb), and subsequently prevented the release of E2F1 from the E2F1/Rb/HDAC1 complex, which ultimately suppressed the growth of CRC cells. Overall, our study suggests that HR488B, a novel and efficient HDAC1 inhibitor, may be a potential candidate for CRC therapy in the future. Furthermore, targeting the E2F1/Rb/HDAC1 axis with HR488B provides a promising therapeutic avenue for CRC.
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Antineoplásicos , Neoplasias Colorrectales , Humanos , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Proteína de Retinoblastoma/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Histona Desacetilasa 1/metabolismoRESUMEN
To explore the impact of heavy metals in pollutant emissions from a coal-fired power plant on the soil environment of surrounding farmland, 31 farmland soil sampling sites were set up with the chimney of the power plant as the center using the radiation ring method. The contents of 10 heavy metals in the soil were determined using inductively coupled plasma mass spectrometry(ICP-MS). The characteristics and potential ecological risks of heavy metals in the soil were analyzed. The spatial differentiation and pollution characteristics of heavy metals were investigated based on geostatistical spatial interpolation and an AERMOD diffusion model, and the source analysis of heavy metals was conducted using a PMF receptor model. The results showed that:â the mean contents of the heavy metals ω(Pb), ω(Mn), ω(Zn), ω(Cr), ω(Ni), ω(Cu), ω(As), ω(Co), ω(Hg), and ω(Cd) in farmland around coal-fired power plants were 414.46, 286.38, 155.22, 69.54, 55.77, 53.48, 31.73, 19.86, 0.78, and 0.71 mg·kg-1, respectively. The contents of Hg, Pb, Cd, As, Zn, and Cu all exceeded the background values of Shaanxi Province by 26, 19.36, 7.88, 2.83, 2.23, 2.49, 1.87, 1.11, and 1.93 times, respectively. â¡ The mean value of the potential ecological risk index(RI) of heavy metals in the soil around the coal-fired power plant was 714.53, indicating a strong ecological risk level, and there were high-value rich areas near the Qianhe railway station and the oil and gas company. The single potential ecological risk index(Ei) of the Hg element was 520.92, which was at a very strong ecological risk level. ⢠The main sources of heavy metals in the soil around the coal-fired power plant were dust removal sources from coal burning(32.16%), industrial and agricultural activities(19.78%), natural sources(26.25%), and traffic sources(21.81%). The high heavy metal content in the soil was distributed in the range of 1-2 km from the power plant, whereas the heavy metal content was low in the range of 1 km from the power plant, increasing gradually in the range of 1-2 km and then decreasing gradually when it was greater than 2 km. The spatial differentiation and enrichment characteristics of heavy metals in farmland around the power plant obtained in this study can provide theoretical and data support for soil pollution control.
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Long noncoding RNAs (lncRNAs) have been associated with a variety of biological activities, including immune responses. However, the function of lncRNAs in antiviral innate immune responses are not fully understood. Here, we identified a novel lncRNA, termed dual function regulating influenza virus (DFRV), elevating in a dose- and time-dependent manner during influenza A virus (IAV) infection, which was dependent on the NFκB signaling pathway. Meanwhile, DFRV was spliced into two transcripts post IAV infection, in which DFRV long suppress the viral replication while DFRV short plays the opposite role. Moreover, DFRV regulates IL-1ß and TNF-α via activating several pro-inflammatory signaling cascades, including NFκB, STAT3, PI3K, AKT, ERK1/2 and p38. Besides, DFRV short can inhibit DFRV long expression in a dose-dependent manner. Collectively, our studies reveal that DFRV may act as a potential dual-regulator to preserve innate immune homeostasis in IAV infection.
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The columnar growth trait of apple (Malus × domestica Borkh.) is genetically controlled by the Columnar (Co) locus on 10 chromosomes, including several candidate genes. Except for MdCo31, other candidate genes at the Co locus are less elucidated. In this study, a strategy of step-by-step screening was adopted to select 11 candidate genes by experimental cloning, transient expression, and genetic transformation. There existed several SNPs in four genes by sequence alignment in columnar and non-columnar apples. Two genes were detected in the nucleus and three genes in the cell membrane, other genes were located in multiple cellular structures by subcellular location. Ectopic expression demonstrated that more branching occurred in MdCo38-OE by upregulating NtPIN1 and NtGA2ox and enlarged leaves in MdCo41-OE tobaccos by upregulating NtCCDs. Transcripts of MdCo38 and MdCo41 were associated with the Co genotypes in apples. The results indicate that MdCo38 and MdCo41 are involved in the columnar growth phenotype in apple, probably through altering polar auxin transport, active gibberellin levels, and strigolactone biosynthesis.
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Malus , Malus/metabolismo , Giberelinas/metabolismo , Fenotipo , Membrana CelularRESUMEN
The tumor microenvironment (TME) is the local environment where malignant cells strive and survive, composed of cancer cells and their surroundings, regulating essential tumor survival, and promotion functions. Dietary flavonoids are abundantly present in common vegetables and fruits and exhibit good anti-cancer activities, which significantly inhibit tumorigenesis by targeting TME constituents and their interaction with cancer cells. This review aims to synthesize information concerning the modulation of TME by dietary flavonoids, as well as to provide insights into the molecular basis of its potential anti-tumor activities, with an emphasis on its ability to control intracellular signaling cascades that regulate the TME processes, involving cell proliferation, invasion and migration, continuous angiogenesis, and immune inflammation. This study will provide a theoretical basis for the development of the leading compound targeting TME for anti-cancer therapies from these dietary flavonoids.
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Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/tratamiento farmacológico , Polifenoles , Frutas , Flavonoides/farmacologíaRESUMEN
Percutaneous electrical nerve stimulation of an injured nerve can promote and accelerate peripheral nerve regeneration and improve function. When performing acupuncture and moxibustion, locating the injured nerve using ultrasound before percutaneous nerve stimulation can help prevent further injury to an already injured nerve. However, stimulation parameters have not been standardized. In this study, we constructed a multi-layer human forearm model using finite element modeling. Taking current density and activated function as optimization indicators, the optimal percutaneous nerve stimulation parameters were established. The optimal parameters were parallel placement located 3 cm apart with the injury site at the midpoint between the needles. To validate the efficacy of this regimen, we performed a randomized controlled trial in 23 patients with median nerve transection who underwent neurorrhaphy. Patients who received conventional rehabilitation combined with percutaneous electrical nerve stimulation experienced greater improvement in sensory function, motor function, and grip strength than those who received conventional rehabilitation combined with transcutaneous electrical nerve stimulation. These findings suggest that the percutaneous electrical nerve stimulation regimen established in this study can improve global median nerve function in patients with median nerve transection.
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To investigate the therapeutic effect of Jingfang Granules on carbon tetrachloride(CCl_4)-induced liver fibrosis in mice and its mechanism. Forty-nine 8-week-old male C57 BL/6 J mice were randomly divided into a blank group, a CCl_4 group, a silybin group(positive control, 100 mg·kg~(-1))+CCl_4, a Jingfang high-dose(16 g·kg~(-1)) group, a Jingfang high-dose(16 g·kg~(-1))+CCl_4 group, a Jingfang medium-dose(8 g·kg~(-1))+CCl_4 group, and a Jingfang low-dose(4 g·kg~(-1))+CCl_4 group, with 7 mice in each group. The mice in the blank group and Jingfang high-dose group were intraperitoneally injected olive oil solution, and mice in other groups were intraperitoneally injected with 10% CCl_4 olive oil solution(5 mL·kg~(-1)) to induce liver fibrosis, twice a week with an interval of 3 d, for 8 weeks. At the same time, except for the blank group and CCl_4 group, which were given deionized water, the mice in other groups were given the corresponding dose of drugs by gavage once daily for 8 weeks with the gavage volume of 10 mL·kg~(-1). All mice were fasted and freely drank for 12 h after the last administration, and then the eyeballs were removed for blood collection. The liver and spleen were collected, and the organ index was calculated. The levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bile acid(TBA), and triglyceride(TG) in the serum of mice were detected by an automated analyzer. Tumor necrosis factor-α(TNF-α), interleukin-6(IL-6) and interleukin-1ß(IL-1ß) levels were detected by enzyme-linked immunosorbent assay(ELISA). Kits were used to detect the contents of superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione(GSH) in the liver tissue. Pathological changes in the liver tissue were observed by hematoxylin-eosin(HE), Masson, and Sirius red staining. Western blot was used to detect protein expressions of transforming growth factor-ß(TGF-ß), α-smooth muscle actin(α-SMA) and Smad4 in the liver tissue. The results indicated that Jingfang Granules significantly reduced the organ index, levels of ALT, AST, TBA,TG, TNF-α, IL-6, and IL-1ß in the serum, and the content of MDA in the liver tissue of mice with CCl_4-induced liver fibrosis. Jingfang Granules also significantly increased the content of SOD and GSH in the liver tissue. Meanwhile, Jingfang Granules down-regulated the protein levels of TGF-ß, α-SMA, and Smad4. Furthermore, Jingfang Granules had no significant effect on the liver tissue morphology and the above indexes in the normal mice. In conclusion, Jingfang Granules has obvious therapeutic effect on CCl_4-induced liver fibrosis, and its mechanism may be related to reducing the expression of pro-inflammatory factors, anti-oxidation, and regulating TGF-ß/Smad4 signaling pathway.
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Interleucina-6 , Factor de Necrosis Tumoral alfa , Ratones , Masculino , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Aceite de Oliva/metabolismo , Aceite de Oliva/farmacología , Aceite de Oliva/uso terapéutico , Tetracloruro de Carbono/efectos adversos , Tetracloruro de Carbono/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Hígado , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Extensive distribution of widespread species and the loss of native species driven by anthropogenic disturbances modify community similarity, resulting in a decrease or increase in community distinctiveness. Data from four basins in the Wannan Mountains, China, were used to evaluate the effects of low-head dams on patterns of fish faunal homogenization and differentiation based on abundance data. We aimed to examine the spatial changes in taxonomic and functional similarities of fish assemblages driven by low-head dams and to examine whether the changes in the similarity of fish assemblages differed between taxonomic and functional components. We found that low-head dams significantly decreased the mean taxonomic similarity but increased the mean functional similarity of fish assemblages in impoundments using abundance-based approaches, suggesting that taxonomic differentiation accompanied functional homogenization in stream fish assemblages. These results show the importance of population abundance in structuring fish faunal homogenization and differentiation at small scales, especially when the major differences among assemblages are in species abundance ranks rather than species identities. Additionally, we also found only a weak positive correlation between changes in mean taxonomic and functional similarities, and partial pairs exhibited considerable variation in patterns of fish faunal homogenization and differentiation for taxonomic and functional components. In conclusion, this study highlighted that the observed taxonomic differentiation of current fish assemblages (short-term phenomenon) is probably an early warning sign of further homogenization in regions where native species are completely predominated and that changes in taxonomic similarity cannot be used to predict changes in functional similarity.
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Immune thrombocytopenia is the most common autoimmune disorder involving blood types. In several studies, the role of T CD4+ cells in patients with immune thrombocytopenia has been associated with different results. Therefore, in this study, with the aim of applied research in the pathogenesis of immune thrombocytopenia, the relationship was investigated between the number of T CD4+ cells, serum levels of IL-11 and IL-17 cytokines, and platelet count. In this regard, 100 patients with immune thrombocytopenia and 100 healthy individuals were included in the study. The T CD4+ cell counts were examined by flow cytometry and in addition, serum levels of interleukins 11 and 17 were measured by ELISA. The results of this study showed that the number of T CD4+ cells and plasma level of IL-17 were not significantly different between the two groups, but plasma levels of IL-11 in the patient group were significantly higher than the control group (P = 0.286). Overall, in this study, the level of cytokine IL-11 was significantly increased in comparison with IL-17 and T CD4+ cells in patients with immune thrombocytopenia, so it is suggested that measurement of cytokine IL-11 level in these patients could be considered as a critical diagnostic marker and indicator in the stages of disease progression.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Trombocitopenia , Citocinas , Humanos , Interleucina-11 , Interleucina-17 , Interleucinas , Linfocitos T Colaboradores-InductoresRESUMEN
Previous studies on the mechanisms of peripheral nerve injury (PNI) have mainly focused on the pathophysiological changes within a single injury site. However, recent studies have indicated that within the central nervous system, PNI can lead to changes in both injury sites and target organs at the cellular and molecular levels. Therefore, the basic mechanisms of PNI have not been comprehensively understood. Although electrical stimulation was found to promote axonal regeneration and functional rehabilitation after PNI, as well as to alleviate neuropathic pain, the specific mechanisms of successful PNI treatment are unclear. We summarize and discuss the basic mechanisms of PNI and of treatment via electrical stimulation. After PNI, activity in the central nervous system (spinal cord) is altered, which can limit regeneration of the damaged nerve. For example, cell apoptosis and synaptic stripping in the anterior horn of the spinal cord can reduce the speed of nerve regeneration. The pathological changes in the posterior horn of the spinal cord can modulate sensory abnormalities after PNI. This can be observed in cases of ectopic discharge of the dorsal root ganglion leading to increased pain signal transmission. The injured site of the peripheral nerve is also an important factor affecting post-PNI repair. After PNI, the proximal end of the injured site sends out axial buds to innervate both the skin and muscle at the injury site. A slow speed of axon regeneration leads to low nerve regeneration. Therefore, it can take a long time for the proximal nerve to reinnervate the skin and muscle at the injured site. From the perspective of target organs, long-term denervation can cause atrophy of the corresponding skeletal muscle, which leads to abnormal sensory perception and hyperalgesia, and finally, the loss of target organ function. The mechanisms underlying the use of electrical stimulation to treat PNI include the inhibition of synaptic stripping, addressing the excessive excitability of the dorsal root ganglion, alleviating neuropathic pain, improving neurological function, and accelerating nerve regeneration. Electrical stimulation of target organs can reduce the atrophy of denervated skeletal muscle and promote the recovery of sensory function. Findings from the included studies confirm that after PNI, a series of physiological and pathological changes occur in the spinal cord, injury site, and target organs, leading to dysfunction. Electrical stimulation may address the pathophysiological changes mentioned above, thus promoting nerve regeneration and ameliorating dysfunction.