RESUMEN
Neutrophil extracellular traps (NETs) are three-dimensional reticular structures that release chromatin and cellular contents extracellularly upon neutrophil activation. As a novel effector mechanism of neutrophils, NETs possess the capacity to amplify localized inflammation and have been demonstrated to contribute to the exacerbation of various inflammatory diseases, including cardiovascular diseases and tumors. It is suggested that lysophosphatidylcholine (LPC), as the primary active component of oxidized low-density lipoprotein, represents a significant risk factor for various inflammatory diseases, such as cardiovascular diseases and neurodegenerative diseases. However, the specific mechanism of NETs formation induced by LPC remains unclear. Quercetin has garnered considerable attention due to its anti-inflammatory properties, serving as a prevalent flavonoid in daily diet. However, little is currently known about the underlying mechanisms by which quercetin inhibits NETs formation and alleviates associated diseases. In our study, we utilized LPC-treated primary rat neutrophils to establish an in vitro model of NETs formation, which was subsequently subjected to treatment with a combination of quercetin or relevant inhibitors/activators. Compared to the control group, the markers of NETs and the expression of P2X7R/P38MAPK/NOX2 pathway-associated proteins were significantly increased in cells treated with LPC alone. Quercetin intervention decreased the LPC-induced upregulation of the P2X7R/P38MAPK/NOX2 pathway and effectively reduced the expression of NETs markers. The results obtained using a P2X7R antagonist/activator and P38MAPK inhibitor/activator support these findings. In summary, quercetin reversed the upregulation of the LPC-induced P2X7R/P38MAPK/NOX2 pathway, further mitigating NETs formation. Our study investigated the potential mechanism of LPC-induced NETs formation, elucidated the inhibitory effect of quercetin on NETs formation, and offered new insights into the anti-inflammatory properties of quercetin.
Asunto(s)
Trampas Extracelulares , Lisofosfatidilcolinas , NADPH Oxidasa 2 , Neutrófilos , Quercetina , Receptores Purinérgicos P2X7 , Proteínas Quinasas p38 Activadas por Mitógenos , Quercetina/farmacología , Lisofosfatidilcolinas/metabolismo , Lisofosfatidilcolinas/farmacología , Trampas Extracelulares/metabolismo , Trampas Extracelulares/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Ratas , Neutrófilos/metabolismo , Neutrófilos/efectos de los fármacos , Receptores Purinérgicos P2X7/metabolismo , NADPH Oxidasa 2/metabolismo , Transducción de Señal/efectos de los fármacos , MasculinoRESUMEN
Coreopsis tinctoria Nutt. is an important medicinal plant in traditional Uyghur medicine. The skin-lightening potential of the flower has been recognized recently; however, the active compounds responsible for that are not clear. In this work, tyrosinase, a target protein for regulating melanin synthesis, was immobilized on the Whatman paper for the first time to screen skin-lightening compounds present in the flower. Quercetagetin-7-O-glucoside (1), marein (2), and okanin (3) were found to be the enzyme inhibitors. The IC50 values of quercetagetin-7-O-glucoside (1) and okanin (3) were 79.06 ± 1.08 µM and 30.25 ± 1.11 µM, respectively, which is smaller than 100.21 ± 0.11 µM of the positive control kojic acid. Enzyme kinetic analysis and molecular docking were carried out to investigate their inhibition mechanism. Although marein (2) showed a weak inhibition effect in vitro, it inhibited the intracellular tyrosinase activity and diminished melanin production in melanoma B16 cells as did the other two inhibitors. The paper-based ligand fishing method developed in this work makes it effective to quickly screen tyrosinase inhibitors from natural products. This is the first report on the tyrosinase inhibitory effect of those three compounds, showing the promising potential of Coreopsis tinctoria for the development of herbal skin-lightening products.
Asunto(s)
Coreopsis , Inhibidores Enzimáticos , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Coreopsis/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Animales , Melaninas/antagonistas & inhibidores , Melaninas/biosíntesis , Ligandos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratones , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/antagonistas & inhibidores , CinéticaRESUMEN
To investigate the protective mechanisms of hydrogen sulfide (H2S) in sepsis-induced acute kidney injury (SAKI), we conducted an in vivo study using a SAKI mouse model induced by intraperitoneal lipopolysaccharide (LPS) injection. Following 6 h of LPS injection, levels of tumor necrosis factor-alpha (TNF-α) and blood urea nitrogen (Bun) were significantly elevated in mouse plasma. In the kidneys of SAKI mice, expression of H2S-generating enzymes cysteinyl-tRNA synthetase (CARS), cystathionine γ-lyase (CSE) and cystathionine ß-synthase (CBS) was markedly downregulated, while glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase (p-PERK/PERK), and B-cell lymphoma-2 recombinant protein X/B-cell lymphoma-2 (Bax/Bcl2) expression was significantly upregulated. H2S improved renal function and attenuated renal histopathological changes in SAKI mice, thereby alleviating LPS-induced endoplasmic reticulum stress (ERS). Additionally, it inhibited the expression of p-PERK/PERK and Bax/Bcl2. After inhibiting CSE activity with dl-propargylglycine (PPG i. p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous H2S influences the pathogenesis of SAKI, while exogenous H2S protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.
RESUMEN
BACKGROUND: Sulfonamide (SA) residues in food of animal origin possess a potential threat to human health and environment. However, due to the polar and ionic characteristics and trace level of SAs and the complexity of food matrices, direct measurement of SAs in these samples is still very difficult. Development of efficient sample pretreatment method for sensitive and selective extraction of trace SAs is of great significance and urgently desired. Therefore, rational design and synthesizing advanced and selective extractants is quite important. RESULTS: In this work, a novel phenazine-based microporous organic network (MON) named TEPM-DP is reasonably synthesized and employed as a packing material for selective solid phase extraction (SPE) and sensitive determination of four typical SAs in milk samples. Phenazine-based monomer with aromatic and heteroaromatic ring and numerous N atoms is chosen to construct TEPM-DP adsorbent to provide π-π, hydrogen bonding, hydrophobic, and electrostatic extraction sites for SAs. The proposed method owns wide linear ranges, low limits of detection, high enrichment factors, and good precisions and recoveries for SAs in complex milk samples. The recoveries of SAs on TEPM-DP are much higher than those of commercial C18 and activated carbon. The extraction mechanisms are also elucidated via FT-IR, XPS, and comparative experiments. SIGNIFICANCE: This work reports the first example of design and synthesizing phenazine-based MON in SPE via a simple and rapid solvothermal method. The results reveal the great prospects of TEPM-DP for enriching polar and ionic SAs in complex samples and uncover the potency of phenazine-based MON in sample pretreatment, which will promote the development of MON.
Asunto(s)
Leche , Fenazinas , Extracción en Fase Sólida , Sulfonamidas , Fenazinas/química , Leche/química , Animales , Sulfonamidas/análisis , Sulfonamidas/aislamiento & purificación , Extracción en Fase Sólida/métodos , Porosidad , Límite de Detección , Adsorción , Contaminación de Alimentos/análisisRESUMEN
Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials.
RESUMEN
Human tissue-resident memory T (TRM) cells play a crucial role in protecting the body from infections and cancers. Recent research observed increased numbers of TRM cells in the lung tissues of idiopathic pulmonary fibrosis patient. However, the functional consequences of TRM cells in pulmonary fibrosis remain unclear. Here, we found that the numbers of TRM cells, especially the CD8+ subset, were increased in the mouse lung with bleomycin-induced pulmonary fibrosis. Increasing or decreasing CD8+ TRM cells in mouse lungs accordingly altered the severity of fibrosis. In addition, adoptive transfer of CD8+ T cells containing a large number of CD8+ TRM cells from fibrotic lungs was sufficient to induce pulmonary fibrosis in control mice. Treatment with CCL18 to induced CD8+ TRM cell expansion and exacerbated fibrosis, while blocking CCR8 prevented CD8+ TRM recruitment and inhibited pulmonary fibrosis. In conclusion, CD8+ TRM cells are essential for bleomycin-induced pulmonary fibrosis, and targeting CCL18/CCR8/CD8+ TRM cells may be a potential therapeutic approach.
RESUMEN
OBJECTIVE: To elucidate the anti-ageing mechanism of the combination of eight ingredients on the skin from a multidimensional view of the skin. METHODS: The target pathway mechanisms of composition to delay skin ageing were investigated by a network pharmacology approach and experimentally validated at three levels: epidermal, dermal, and tissue. RESULTS: We identified 24 statistically significant skin ageing-related pathways, encompassing crucial processes such as epidermal barrier repair, dermal collagen and elastin production, inhibition of reactive oxygen species (ROS), as well as modulation of acetylcholine and acetylcholine receptor binding. Furthermore, our in vitro experimental findings exhibited the following outcomes: the composition promotes fibroblast proliferation and the expression of barrier-related genes in the epidermis; it also stimulated the expression of collagen I, collagen III, and elastic fibre while inhibiting ROS and ß-Gal levels in HDF cells within the dermis. Additionally, Spilanthol in the Acmella oleracea extract contained in the composition demonstrated neuro-relaxing activity in Zebrafish embryo, suggesting its potential as an anti-wrinkle ingredient at the hypodermis level. CONCLUSIONS: In vitro experiments validated the anti-ageing mechanism of composition at multiple skin levels. This framework can be extended to unravel the functional mechanisms of other clinically validated compositions, including traditional folk recipes utilized in cosmeceuticals.
OBJECTIF: Élucider le mécanisme antiâge de la combinaison de huit ingrédients sur la peau d'un point de vue multidimensionnel. MÉTHODES: Les mécanismes des voies cibles de la composition pour retarder le vieillissement de la peau ont été étudiés par une approche de pharmacologie des réseaux et validés expérimentalement à trois niveaux : épidermique, dermique et tissulaire. RÉSULTATS: Nous avons identifié 24 voies statistiquement significatives liées au vieillissement de la peau, englobant des processus cruciaux tels que la réparation de la barrière épidermique, la production de collagène et d'élastine dermiques, l'inhibition des espèces réactives de l'oxygène (ROS), ainsi que la modulation de l'acétylcholine et de la liaison des récepteurs de l'acétylcholine. En outre, nos résultats expérimentaux in vitro ont montré les résultats suivants : la composition favorise la prolifération des fibroblastes et l'expression des gènes liés à la barrière dans l'épiderme ; elle stimule également l'expression du collagène I, du collagène III et de la fibre élastique tout en inhibant les niveaux de ROS et de ßGal dans les cellules HDF au sein du derme. En outre, le Spilanthol de l'extrait d'Acmella oleracea contenu dans la composition a démontré une activité neurorelaxante dans l'embryon de poisson zèbre, suggérant son potentiel en tant qu'ingrédient antirides au niveau de l'hypoderme. CONCLUSIONS: Les expériences in vitro ont validé le mécanisme antiâge de la composition à plusieurs niveaux de la peau. Ce cadre peut être étendu pour élucider les mécanismes fonctionnels d'autres compositions validées cliniquement, y compris les recettes populaires traditionnelles utilisées dans les produits cosméceutiques.
RESUMEN
Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 µM prodrug floxuridine oligomers and 16 µg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.
RESUMEN
BACKGROUND: An ependymoma is a glial tumor that usually occurs in or near the ventricle, close to the ependyma. It rarely occurs exclusively in the brain parenchyma without being associated with the ventricle. CASE SUMMARY: Here, we report a rare case of a cerebellar ependymoma completely located in the brain parenchyma. A previously healthy 32-year-old female with a 1-month history of dizziness was admitted to our hospital. During hospitalization, magnetic resonance imaging of the brain revealed a space-occupying lesion measuring 57 mm × 41 mm × 51 mm in the right cerebellar hemisphere and inferior cerebellar vermis. The patient underwent surgical resection for the right cerebellar mass. Postoperative pathological examination revealed an ependymoma. At 1 year follow-up, the patient was doing well and showed no recurrence. CONCLUSION: We conducted a literature review and summarized three theories regarding ependymomas located exclusively in the brain parenchyma, which are key to the diagnosis of intraparenchymal cerebellar ependymomas. Surgery and postoperative radiotherapy are the primary treatment options for ependymomas.
RESUMEN
Petroleum pollution has become a prominent global environmental problem, restricting the coordinated development of the economy and the ecological environment. Although bioremediation has the advantages of low carbon, high efficiency, and safety, the complexity and severity of the pollution makes it difficult to achieve the remediation purpose with a single bioremediation. Ecological remediation based on bioremediation can integrate carbon neutrality and ecological environmental protection, synergistically promote pollution reduction and carbon reduction, ensure the sustainability of soil and sediment to fulfil ecosystem service functions, and ultimately achieve soil health and sediment health. Therefore, the transition from bioremediation to ecological restoration is the optimal choice for environmental management and ecosystem maintenance at this stage. Here, we first analyzed the micro-removal mechanism of petroleum hydrocarbons in different bioremediation techniques and discussed the types and characteristics of different bioremediation techniques from an ecological point of view. Based on this, the necessity of bioremediation for ecological restoration was analyzed in detail. Finally, a reasonable outlook on the development of ecological remediation is given to provide theoretical support for optimizing ecological remediation of petroleum pollution.
RESUMEN
Ergosterols are essential components of fungal plasma membranes. Inhibitors targeting ergosterol biosynthesis (ERG) genes are critical for controlling fungal pathogens, including Magnaporthe oryzae, the fungus that causes rice blast. However, the translational mechanisms governing ERG gene expression remain largely unexplored. Here, we show that the Trm6/Trm61 complex catalyzes dynamic N1-methyladenosine at position 58 (m1A58) in 51 transfer RNAs (tRNAs) of M. oryzae, significantly influencing translation at both the initiation and elongation stages. Notably, tRNA m1A58 promotes elongation speed at most cognate codons mainly by enhancing eEF1-tRNA binding rather than affecting tRNA abundance or charging. The absence of m1A58 leads to substantial decreases in the translation of ERG genes, ergosterol production, and, consequently, fungal virulence. Simultaneously targeting the Trm6/Trm61 complex and the ergosterol biosynthesis pathway markedly improves rice blast control. Our findings demonstrate an important role of m1A58-mediated translational regulation in ergosterol production and fungal infection, offering a potential strategy for fungicide development.
RESUMEN
BACKGROUND: We previously optimized the duration and dose of vonoprazan and amoxicillin dual therapy in China. The efficacy of vonoprazan with b.i.d. amoxicillin in comparison with vonoprazan-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection has not been adequately evaluated. METHODS: In a non-inferiority, randomized clinical trial, H. pylori infected and treatment-naïve patients were randomly assigned to receive 14 days of either vonoprazan dual (vonoprazan 20 mg and amoxicillin 1 g twice daily) or quadruple therapy (vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth potassium citrate 600 mg twice daily). H. pylori status was confirmed using 13C-urea breath tests or fecal antigen test. The primary outcome was the H. pylori eradication rate following vonoprazan dual and quadruple therapy at 4-12 weeks. We also compared drug compliance to either regimen and documented their side effect. RESULTS: A total of 190 subjects were randomized. The eradication rate of vonoprazan dual and quadruple therapy were 87.4% and 92.6% (p = 0.23) by intention-to-treat analysis, respectively, and 96.5% and 97.7% (p = 0.63) by per-protocol analysis, respectively. The efficacy of vonoprazan dual therapy was non-inferior to vonoprazan-containing quadruple therapy in per-protocol analysis (p < 0.001; difference: -1.2%; 90% confidence interval: -5.4% to 3.0%). CONCLUSION: Vonoprazan with b.i.d. amoxicillin for 14 days provided similar satisfactory efficacy with vonoprazan-containing quadruple therapy as a first-line H. pylori treatment in China.
Asunto(s)
Amoxicilina , Antibacterianos , Quimioterapia Combinada , Infecciones por Helicobacter , Helicobacter pylori , Pirroles , Sulfonamidas , Humanos , Infecciones por Helicobacter/tratamiento farmacológico , Pirroles/uso terapéutico , Pirroles/administración & dosificación , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Amoxicilina/uso terapéutico , Amoxicilina/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Helicobacter pylori/efectos de los fármacos , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Adulto , Resultado del Tratamiento , China , Anciano , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificaciónRESUMEN
OBJECTIVE: Our study aimed to investigate the association between maternal pre-pregnancy body mass index (BMI), gestational weight gain (GWG), and impaired pelvic floor muscle (PFM) morphology and function during the early postpartum period. METHODS: This retrospective cohort study was conducted at Shanghai First Maternity and Infant Hospital from December 2020 to December 2022. A total of 1118 primiparous women with singleton pregnancies who underwent vaginal deliveries and participated in postpartum PFM assessments were included. Maternal pre-pregnancy BMI and GWG were considered as exposures. PFM morphology and function impairment were the primary outcomes. PFM morphology impairment, defined as levator ani muscle avulsion, was assessed using transperineal ultrasound. PFM function impairment, manifested as diminished PFM fiber strength, was assessed through vaginal manometry. Multivariable logistic regression analysis was employed to calculate adjusted odds ratios (aOR) with 95% confidence intervals (CI). Restricted cubic spline models were used to validate and visualize the relationship. RESULTS: Women with lower pre-pregnancy BMI were at an increased risk of levator ani muscle avulsion (aOR = 1.73, 95% CI: 1.10-2.70, P = 0.017), particularly when combined with excessive GWG during pregnancy (aOR = 3.20, 95% CI: 1.15-8.97, P = 0.027). Lower pre-pregnancy BMI was also identified as an independent predictor of PFM weakness (aOR = 1.53, 95% CI: 1.08-2.16, P = 0.017 for type I fiber injuries). Notably, regardless of the avulsion status, both underweight and overweight/obese women faced an elevated risk of reduced PFM strength (aOR = 1.74, 95% CI: 1.17-2.59, P = 0.006 for underweight women with type I fiber injuries; aOR = 1.67, 95% CI: 1.06-2.64, P = 0.027; and aOR = 1.73, 95% CI: 1.09-2.76, P = 0.021 for overweight/obese women with type I and type II fibers injuries, respectively). CONCLUSIONS: Both lower and higher pre-pregnancy BMI, as well as excessive GWG, were strongly associated with PFM impairments. These findings highlighted the critical importance of comprehensive weight management throughout pregnancy to effectively promote women's pelvic health.
RESUMEN
AIM: To describe the surgical procedure of fusiform penetrating keratoplasty (FPK) using multiple trephines of different sizes for treating patients with severe infectious keratitis. METHODS: Fourteen eyes underwent FPK, and 15 eyes received conventional penetrating keratoplasty (PK) were included in the study. The best-corrected visual acuity (BCVA), refractive outcomes, endothelial cell density, and postoperative complications were recorded. RESULTS: The FPK group was followed for an average of 15.3±2.1mo, whereas the PK group was followed for 16.1±1.9mo. The corneal ulcers were elliptical-shaped in all 14 eyes in the FPK group. The mean BCVA (logMAR, 0.26±0.13) showed no statistically significant differences from that in the PK group (logMAR, 0.21±0.12, P>0.05) at 1y after surgery. But the mean curvature, mean astigmatism, and mean spherical equivalent in the FPK group were lower than those in the PK group (P<0.05). Peripheral anterior synechia was observed in one patient in the FPK group, whereas 6 patients in the PK group. Suture loosening and neovascularization were observed in 4 and 5 eyes in the PK group, respectively. No graft immune rejection or elevation of intraocular pressure was observed in the two groups. CONCLUSION: For patients with elliptical-shaped corneas or corneal ulcers, FPK can avoid disrupting of corneal limbus, reduce the risk of postoperative complications, and can result in satisfactory visual quality.
RESUMEN
BACKGROUND: The aim of this study was to investigate the epidemiological characteristics and antibiotic resistance patterns of Ureaplasma urealyticum (UU) infection among women and children in southwest China. METHODS: A total of 8,934 specimens, including urogenital swabs and throat swabs were analyzed in this study. All samples were tested using RNA-based Simultaneous Amplification and Testing (SAT) methods. Culture and drug susceptibility tests were performed on UU positive patients. RESULTS: Among the 8,934 patients, the overall positive rate for UU was 47.92%, with a higher prevalence observed among women of reproductive age and neonates. The majority of UU positive outpatients were women of reproductive age (88.03%), while the majority of UU positive inpatients were neonates (93.99%). Overall, hospitalization rates due to UU infection were significantly higher in neonates than in women. Further analysis among neonatal inpatients revealed a higher incidence of preterm birth and low birth weight in UU positive inpatients (52.75% and 3.65%, respectively) than in UU negative inpatients (44.64% and 2.89%, respectively), especially in very preterm and extremely preterm neonates. Moreover, the incidence rate of bronchopulmonary dysplasia (BPD) among hospitalized neonatal patients was significantly higher in the UU positive group (6.89%) than in the UU negative group (4.18%). The drug susceptibility tests of UU in the neonatology, gynecology and obstetrics departments exhibited consistent sensitivity patterns to antibiotics, with high sensitivity to tetracyclines and macrolides, and low sensitivity to fluoroquinolones. Notably, UU samples collected from the neonatology department exhibited significantly higher sensitivity to azithromycin and erythromycin (93.8% and 92.9%, respectively) than those collected from the gynecology and obstetrics departments. CONCLUSIONS: This study enhances our understanding of the current epidemiological characteristics and antibiotic resistance patterns of UU infection among women and children in southwest China. These findings can aid in the development of more effective intervention, prevention and treatment strategies for UU infection.
Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Infecciones por Ureaplasma , Ureaplasma urealyticum , Humanos , Infecciones por Ureaplasma/epidemiología , Infecciones por Ureaplasma/microbiología , Infecciones por Ureaplasma/tratamiento farmacológico , Ureaplasma urealyticum/efectos de los fármacos , Ureaplasma urealyticum/aislamiento & purificación , Ureaplasma urealyticum/genética , Femenino , China/epidemiología , Recién Nacido , Antibacterianos/farmacología , Adulto , Masculino , Adolescente , Lactante , Persona de Mediana Edad , Adulto Joven , Preescolar , Niño , PrevalenciaRESUMEN
Sensory experience affects not only the corresponding primary sensory cortex, but also synaptic and neural circuit functions in other brain regions in a cross-modal manner. However, it remains unclear whether oligodendrocyte (OL) generation and myelination can also undergo cross-modal modulation. Here, we report that while early life short-term whisker deprivation from birth significantly reduces in the number of mature of OLs and the degree of myelination in the primary somatosensory cortex(S1) at postnatal day 14 (P14), it also simultaneously affects the primary visual cortex (V1), but not the medial prefrontal cortex (mPFC) with a similar reduction. Interestingly, when mice were subjected to long-term early whisker deprivation from birth (P0) to P35, they exhibited dramatically impaired myelination and a deduced number of differentiated OLs in regions including the S1, V1, and mPFC, as detected at P60. Meanwhile, the process complexity of OL precursor cells (OPCs) was also rduced, as detected in the mPFC. However, when whisker deprivation occurred during the mid-late postnatal period (P35 to P50), myelination was unaffected in both V1 and mPFC brain regions at P60. In addition to impaired OL and myelin development in the mPFC, long-term early whisker-deprived mice also showed deficits in social novelty, accompanied by abnormal activation of c-Fos in the mPFC. Thus, our results reveal a novel form of cross-modal modulation of myelination by sensory experience that can lead to abnormalities in social behavioral, suggesting a possible similar mechanism underlying brain pathological conditions that suffer from both sensory and social behavioral deficits, such as autism spectrum disorders.
Asunto(s)
Ratones Endogámicos C57BL , Vaina de Mielina , Corteza Prefrontal , Privación Sensorial , Corteza Somatosensorial , Vibrisas , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Vibrisas/fisiología , Privación Sensorial/fisiología , Vaina de Mielina/fisiología , Vaina de Mielina/metabolismo , Corteza Somatosensorial/fisiología , Ratones , Oligodendroglía/fisiología , Oligodendroglía/metabolismo , Animales Recién Nacidos , Masculino , Conducta Exploratoria/fisiología , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo , Corteza Visual/fisiología , Conducta Social , FemeninoRESUMEN
Metal-based chemoimmunotherapy has recently garnered significant attention for its capacity to stimulate tumor-specific immunity beyond direct cytotoxic effects. Such effects are usually caused by ICD via the activation of DAMP signals. However, metal complexes that can elicit antitumor immune responses other than ICD have not yet been described. Herein, we report that a rhodium complex (Rh-1) triggers potent antitumor immune responses by downregulating Wnt/ß-catenin signaling with subsequent activation of T lymphocyte infiltration to the tumor site. The results of mechanistic experiments suggest that ROS accumulation following Rh-1 treatment is a critical trigger of a decrease in ß-catenin and enhanced secretion of CCL4, a key mediator of T cell infiltration. Through these properties, Rh-1 exerts a synergistic effect in combination with PD-1 inhibitors against tumor growth in vivo. Taken together, our work describes a promising metal-based antitumor agent with a noncanonical mode of action to sensitize tumor tissues to ICB therapy.
Asunto(s)
Antineoplásicos , Rodio , Vía de Señalización Wnt , Rodio/química , Rodio/farmacología , Animales , Vía de Señalización Wnt/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Humanos , Ratones , beta Catenina/metabolismo , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/uso terapéutico , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BLRESUMEN
Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Gefitinib , Indoles , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Quinolinas , Humanos , Gefitinib/administración & dosificación , Gefitinib/efectos adversos , Gefitinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Indoles/administración & dosificación , Indoles/uso terapéutico , Indoles/efectos adversos , Masculino , Femenino , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más AñosRESUMEN
The coal gangue dump may introduce heavy metal(oid)s (HMs) into surrounding agricultural soils, posing potential health risks to nearby communities. This study evaluated heavy metal(oid) pollution in agricultural soils adjacent to a gangue dump at an abandoned coal mine in Chongqing, Southwest China. The concentrations of HMs (As, Cd, Cr, Cu, Ni, Pb, and Zn) were quantified using ICP-MS, and the contamination status was assessed using the Geoaccumulation Index (Igeo), Contamination Factor (CF), Pollution Load Index (PLI), and Potential Ecological Risk Index (RI). Heavy metal(oid) contamination was detected in soils across a depth of 0-30 cm, particularly pronounced in the topsoil layer (0-10 cm and 10-20 cm depths). Cu emerged as the predominant contaminant across all examined depths, with average Igeo values of 1.20, 1.21, and 1.16 for the 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively, indicating moderate contamination. The CF for Cu was 3.55, 3.55, and 3.50 for these respective depths, classifying it as considerable contamination. The PLI values ranged from 1.61 to 2.50, with a mean value of 2.12, indicating overall contamination. The ecological risk assessment indicated that the soil's ecological risk was low at all depths. Cd was the major contributor to the RI, accounting for 48%, 47%, and 42% at 0-10 cm, 10-20 cm, and 20-30 cm depths, respectively. Health risk assessments revealed significant non-carcinogenic risks to children (mean HI = 1.30) and unacceptable carcinogenic risks to both adults and children (mean TCR = 3.26 × 10-4 and 1.53 × 10-3, respectively). This study underscores the critical need for comprehensive risk assessments using multiple indicators to prioritize remediation efforts for HMs, providing a scientific basis for effective environmental management and public health protection in the Three Gorges Reservoir Area.
Asunto(s)
Minas de Carbón , Monitoreo del Ambiente , Metales Pesados , Contaminantes del Suelo , Metales Pesados/análisis , China , Contaminantes del Suelo/análisis , Humanos , Medición de Riesgo , Monitoreo del Ambiente/métodos , Agricultura , Suelo/química , Contaminación Ambiental/análisis , Contaminación Ambiental/efectos adversos , Carbón Mineral/análisisRESUMEN
The sudden change in the environment from a dark, low-oxygen, low-temperature, high-humidity underground stable environment to an environment with much-improved temperature and humidity, a high oxygen content, enhanced light exposure, and increased harmful organisms has greatly affected the stability of the ivory unearthed from the Sanxingdui site. Therefore, the implementation of an effective emergency protection strategy for ivory excavated at Sanxingdui is imperative and urgently needed. However, the current gauze technique used at many archaeological sites suffers from short timescales, poor transparency of the material, and susceptibility to reverse osmosis of the ivory. Therefore, in this study, a transparent poly(acrylamide-acrylic acid) (P(AM-AA)) hydrogel-poly(dimethylsiloxane) (PDMS) elastomer bilayer was designed for the effective protection of excavated ivory. In this system, a hydrophobic PDMS elastomer was constructed on the surface of the hydrogel by the introduction of a silane coupling agent to inhibit the loss of water from the hydrogel to the external environment, thus prolonging the preservation of ivory by the protective material. The covalent interface between the hydrogel and the elastomer allowed the double-layer composite to exhibit excellent interfacial bonding. In addition, the double-layer material demonstrated a high mechanical strength of 1.2 MPa and a water binding ratio of â¼31%, which allowed it to form strong hydrogen bonds with the silanol structure. When the hydrogel was placed in an air environment (temperature: 25 °C; relative humidity: 65% RH), the water-retention rate of the double-layer material was still more than 60% after 5 days, thus the double-layer material showed excellent performance. Meanwhile, the double-layer material had a transmittance of more than 90% and exhibited a high degree of transparency, which makes it possible to promptly observe the changes occurring on the surface of the ivory. The combination of the aforementioned properties makes the bilayer a promising material for moisturizing and protecting excavated ivory in situ. Based on these properties, we used the prepared P(AM-AA)/PDMS double-layer material directly for wrapping the K8 ivory with the highest water content at Sanxingdui. The weight retention rate of the ivory was around 70% after 50 days of placement (temperature: 25 °C; relative humidity: 60% RH), the macroscopic morphology did not change significantly and the mechanical properties of the wrapped ivory were basically unchanged, which indicated that the double-layer material has an excellent on-site protection effect on the ivory excavated from Sanxingdui. This work provides new ideas and methods for the temporary conservation of wet heritage.