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Promoter methylation is one of the most studied epigenetic modifications and it is highly relevant to the onset and progression of thyroid carcinoma (THCA). This study investigates the promoter methylation and expression pattern of intercellular adhesion molecule 5 (ICAM5) in THCA. CpG islands with aberrant methylation pattern in THCA, and the expression profiles of the corresponding genes in THCA, were analyzed using bioinformatics. ICAM5 was suggested to have a hypermethylation status, and it was highly expressed in THCA tissues and cells. Its overexpression promoted proliferation, mobility, and tumorigenic activity of THCA cells. As for the downstream signaling, ICAM5 was found to activate the MAPK/ERK and MAPK/JNK signaling pathways. Either inhibition of ERK or JNK blocked the oncogenic effects of ICAM5. DNA methyltransferases 1 (DNMT1) and DNMT3a were found to induce promoter hypermethylation of ICAM5 in THCA cells. Knockdown of DNMT1 or DNMT3a decreased the ICAM5 expression and suppressed malignant properties of THCA cells in vitro and in vivo, which were, however, restored by further artificial ICAM5 overexpression. Collectively, this study reveals that DNMT1 and DNMT3a mediates promoter hypermethylation and transcription activation of ICAM5 in THCA, which promotes malignant progression of THCA through the MAPK signaling pathway.
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ADN (Citosina-5-)-Metiltransferasas , Neoplasias de la Tiroides , Humanos , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Activación Transcripcional , Metilación de ADN , Neoplasias de la Tiroides/genética , Proteínas del Tejido Nervioso/genética , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismoRESUMEN
Limbal epithelial stem/progenitor cells (LESCs) proliferate, migrate and differentiate into mature corneal epithelium cells (CECs) that cover the ocular surface. LESCs play a crucial role in the maintenance and regeneration of the corneal epithelium, and their dysfunction can lead to various corneal diseases. Neuregulin 1 (NRG1) is a member of the epidermal growth factor family that regulates the growth and differentiation of epithelial tissues. Here, we depicted the dynamic transcriptomic profiles during human CEC differentiation, identifying six gene co-expression modules that were specific to different differentiation stages. We found that the expression of NRG1 was high in human LESCs and decreased dramatically upon differentiation. Knockdown of NRG1 significantly inhibited LESC proliferation and upregulated the expression of the terminal differentiation marker genes KRT3, KRT12 and CLU. In addition, the scratch wound closure assay showed that knockdown of NRG1 attenuated wound closure of LESCs over 24 h. Together, we dissected the transcriptional regulatory dynamics during CEC differentiation and identified NRG1 as a key regulator that promoted LESC proliferation and migration and maintained the undifferentiated state.
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OBJECTIVE: According to the different characteristics of patients and cervical lymph node metastasis of oral and oropharyngeal cancer, the marginal mandibular branches of facial nerves were treated by different surgical procedures, and the safety and protective effects of different surgical procedures were investigated. METHODS: One hundred ninety-seven patients with oral and oropharyngeal cancer satisfying the inclusion criteria were selected. According to the different characteristics of patients and cervical metastatic lymph nodes, three different surgical procedures were used to treat the marginal mandibular branches of the facial nerve: finding and exposing the marginal mandibular branches of the facial nerves at the mandibular angles of the platysma flaps, finding and exposing the marginal mandibular branches of facial nerves at the intersections of the distal ends of facial arteries and veins with the mandible, and not exposing the marginal mandibular branches of the facial nerves. The anatomical position, injury, and complications of the marginal mandibular branches of the facial nerves were observed. RESULTS: The marginal mandibular branches of the facial nerves were found and exposed at the mandibular angles of the platysma flaps in 102 patients; the marginal mandibular branches of facial nerves were found and exposed at the intersections of the distal ends of the facial arteries and veins with the mandibles in 64 patients; the marginal mandibular branches of facial nerves were not exposed in 31 patients; among them, four patients had permanent injury of the marginal mandibular branches of the facial nerves, and temporary injury occurred in seven patients. There were statistically significant differences in the protection of the mandibular marginal branch of the facial nerve among the three different surgical methods (P = 0.0184). The best protective effect was to find and expose the mandibular marginal branch of the facial nerve at the mandibular angle of the platysma muscle flap, and the injury rate was only 2.94%. CONCLUSION: The three different surgical procedures were all safe and effective in treating the marginal mandibular branches of the facial nerves, the best protective effect was to find and expose the mandibular marginal branch of the facial nerve at the mandibular angle of the platysma muscle flap.
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Nervio Facial , Neoplasias Orofaríngeas , Humanos , Escisión del Ganglio Linfático , Neoplasias Orofaríngeas/cirugía , Ganglios Linfáticos/cirugía , Metástasis LinfáticaRESUMEN
A series of highly fluorinated polyimide/allomelanin nanoparticles (FPI/AMNPs) films were prepared with FPI as the matrix and AMNPs as the filler. Due to the formation of hydrogen bonds, significantly reinforced mechanical and UV-shielding properties are acquired. Stress-strain curves demonstrated a maximum tensile strength of 150.59 MPa and a fracture elongation of 1.40% (0.7 wt.% AMNPs), respectively, 1.78 and 1.56× that of pure FPI. The measurements of the UV-vis spectrum, photodegradation of curcumin and repeated running tests confirmed the splendid UV-shielding capabilities of FPI/AMNPs films. The enhancement mechanisms, such as synergistic UV absorption of the charge transfer complexes in FPI and AMNPs and photothermal conversion, were the reasons for its exceptional UV shielding. The excellent comprehensive properties above enable FPI/AMNPs nanocomposites to be potential candidates in the field of UV shielding.
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Piezo1 (also known as Fam38A) is a mechanosensing channel required for mechanotransduction in various cell types. In astrocytes, Piezo1 activation is associated with the pathogenesis of central nervous system neurodegeneration. Expression of Piezo1 has been detected in mouse optic nerve head astrocytes, however, the functional role of Piezo1 has not been identified. In this study, we investigated the role of Piezo1 in optic nerve head astrocyte reactivity. Primary mouse optic nerve head astrocytes were cultured and subjected to mechanical stretch. The expression level of Piezo1 was determined by quantitative PCR and immunocytochemistry staining. Astrocytes were further treated with Yoda1, a specific Piezo1 agonist. The intracellular calcium concentration and expression of F-actin and fibronectin were determined in Yoda1 treated cells. We found that mechanical stretch activated Piezo1 in optic nerve head astrocytes. Yoda1 induced robust Ca2+ responses in a dose dependent manner. In addition, Yoda1 treated cells showed a redistribution of F-actin cytoskeleton and an increased expression of fibronectin which indicated astrocyte reactivity. Our results suggest that Piezo1 responses to mechanical stimulation and plays a role in astrocyte reactivity. This study provides new insights into optic nerve head astrocyte mechanotransduction.
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Astrocitos/metabolismo , Canales Iónicos/fisiología , Disco Óptico/metabolismo , Animales , Biomarcadores/metabolismo , Calcio/metabolismo , Células Cultivadas , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C57BL , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Estrés MecánicoRESUMEN
Podocytes are highly specialized cells that play an essential role in maintaining the integrity and function of the glomerular filtration barrier. Wilms tumor 1 (WT1) and ß-catenin are two master regulators that play opposing roles in podocyte biology and mutually antagonize each other. However, exactly how ß-catenin inhibits WT1 remains incompletely understood. In this study, we demonstrated the role of miR-466o-3p in mediating ß-catenin-triggered podocyte injury by targeting WT1. The expression of miR-466o-3p was upregulated in cultured podocytes after ß-catenin activation and in glomerular podocytes in adriamycin (ADR) nephropathy, remnant kidney after 5/6 renal ablation, and diabetic kidney disease. Bioinformatics analysis and luciferase reporter assay confirmed that miR-466o-3p directly targeted WT1 mRNA. Furthermore, overexpression of miR-466o-3p downregulated WT1 protein and promoted podocyte injury in vitro. Conversely, inhibition of miR-466o-3p alleviated ß-catenin-induced podocyte dysfunction. In mouse model of ADR nephropathy, overexpression of miR-466o-3p inhibited WT1, aggravated podocytes injury and deteriorated proteinuria. In contrast, inhibition of renal miR-466o-3p by antagomiR, either prior to or after ADR injection, substantially restored WT1, alleviated podocytes injury and reduced renal fibrosis. These studies reveal a critical role for miR-466o-3p, a novel microRNA that has not been characterized previously, in mediating ß-catenin-triggered WT1 inhibition. Our findings also uncover a new pathogenic mechanism by which ß-catenin promotes podocyte injury and proteinuria in glomerular diseases.
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MicroARNs/metabolismo , Podocitos/metabolismo , Insuficiencia Renal Crónica/metabolismo , Proteínas WT1/genética , beta Catenina/metabolismo , Animales , Antagomirs/uso terapéutico , Línea Celular , Células Cultivadas , Doxorrubicina/toxicidad , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/etiología , Proteínas WT1/metabolismoRESUMEN
The initial nonadiabatic decay dynamics of E,E-2,4-hexadienal (HAL) in the light absorbing S2(ππ*) state were studied using resonance Raman spectroscopy and complete-active space self-consistent field (CASSCF) calculations. The UV and vibrational spectra were assigned on the basis of the UV absorption, Fourier transform (FT)-Raman and FT-infrared measurements, the density-functional theory computations, and the normal mode analysis. The A-band resonance Raman spectra in cyclohexane and acetonitrile were obtained at 282.4, 273.9, 266.0, 252.7, and 245.9 nm excitation wavelengths, respectively, to probe the corresponding structural dynamics of HAL. The A-band absorption cross section and the corresponding absolute resonance Raman cross sections were simulated using a simple model based on the time-dependent wave-packet theory in a Brownian oscillator model. The geometric structures of the singlet electronic excited states and their curve-crossing points were optimized at the CASSCF level of theory. The obtained short-time structural dynamics in easy-to-visualize internal coordinates were then compared with the CASSCF-predicted structural-parameter changes of S2(ππ*)S1(nπ*)-n (n = 1-4). Our results indicate that the initial population of HAL in the S2 state ramifies in or nearby the Franck-Condon (FC) region, leading to five S2(ππ*) â S1(nπ*) internal conversion pathways due to the flexibility of the molecular chain and the different electronic resonant structures formed nearby FC of the S2 state. Then, the formed S1 transient species, which have different geometric structures and different energy partitions, undergo different photophysical processes, such as S1 â S0 internal conversion, S1 â T1 intersystem crossing, and the S1 â S'1 photoisomerization reaction. The substitution effect on the S2(ππ*) â S1(nπ*) internal conversion dynamics and the trans-cis photoisomerization reaction is proposed in terms of the p-π conjugation interaction or the p-σ superconjugation interaction.
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Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4A Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4A Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of ß-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated ß-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A, p19ARF, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-ß1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a-TGF-ß pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.
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Senescencia Celular/fisiología , Riñón/patología , Insuficiencia Renal Crónica/patología , Proteínas Wnt/fisiología , Vía de Señalización Wnt , Animales , Línea Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Modelos Animales de Enfermedad , Células Epiteliales/patología , Fibroblastos/efectos de los fármacos , Fibrosis , Regulación de la Expresión Génica , Genes p16 , Humanos , Riñón/irrigación sanguínea , Túbulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Interferencia de ARN , Ratas , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factor de Crecimiento Transformador beta/fisiología , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Proteínas Wnt/antagonistas & inhibidores , Proteínas Wnt/genéticaRESUMEN
AIM: We aimed to investigate the association between systemic immune-inflammation index (SII) and the clinical outcomes in patients with advanced non-small-cell lung cancer. MATERIALS & METHODS: The SII was calculated as platelet (P) × neutrophil (N)/lymphocyte (L), and the data were obtained within 1 week before treatment. Kaplan-Meier analysis and Cox proportional hazard models were used to assess the prognostic value of SII. RESULTS: Kaplan-Meier analyses revealed that the higher SII group was associated with poorer progression-free survival (p < 0.001) and poorer overall survival (p < 0.001). Multivariable Cox analysis further revealed SII as an independent prognostic factor for overall survival (p = 0.010) and progression-free survival (p = 0.001). CONCLUSION: SII can serve as a useful biomarker to predict recurrence and death for patients with advanced non-small-cell lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/inmunología , Inflamación/mortalidad , Neoplasias Pulmonares/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Plaquetas , Antígeno Carcinoembrionario/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
A new theoretical method was established for the combinatorial calculation of the dissociation rate constant (K-1) of the metal-organic complexes (MLs), the concentration of free ionic soil metals (CM), the labile concentration of soil metal-organic complexes (CML) based on diffusive gradients in thin-films (DGT) technique with a range of diffusive layer thicknesses (0.053-0.173â¯mm) in soils. The fitting results agreed well with the determined values. The values of K-1, CML and CM were calculated without other morphological analysis software and the fitting results agreed well with the determined values with some advantages such as the use of fewer hypothetical parameters, ease of calculation, the full embodiment of the contribution of MLs to the labile content. According to the results of model fitting, cation exchange capacity and soil organic matter were found to be the key environmental factors for K-1 values of Cd and Ni, respectively. The labile contents of Cd and Ni in soil were closely related with pH, soil organic matter and the total contents of heavy metals.
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Cadmio/análisis , Monitoreo del Ambiente/métodos , Níquel/análisis , Contaminantes del Suelo/análisis , Suelo/química , Difusión , CinéticaRESUMEN
Phormidium tenue, a cyanobacterium that grows in the topsoil of biological soil crusts (BSCs), has the highest recovery rate among desert crust cyanobacteria after exposure to ultraviolet B (UV-B) radiation. However, the mechanism underlying its recovery process is unclear. To address this issue, we measured chlorophyll a fluorescence, generation of reactive oxygen species (ROS), lipid peroxidation, and repair of DNA breakage in P. tenue following exposure to UV-B. We found that UV-B radiation at all doses tested reduced photosynthesis and induced cell damage in P. tenue. However, P. tenue responded to UV-B radiation by rapidly reducing photosynthetic activity, which protects the cell by leaking less ROS. Antioxidant enzymes, DNA damage repair systems, and UV absorbing pigments were then induced to mitigate the damage caused by UV-B radiation. The addition of exogenous antioxidant chemicals ascorbate and N-acetylcysteine also mitigated the harmful effects caused by UV-B radiation and enhanced the recovery process. These chemicals could aid in the resistance of P. tenue to the exposure of intense UV-B radiation in desertified areas when inoculated onto the sand surface to form artificial algal crusts.
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Clorofila/metabolismo , Cianobacterias/efectos de la radiación , Roturas del ADN/efectos de la radiación , Fotosíntesis/efectos de la radiación , Rayos Ultravioleta , Antioxidantes/metabolismo , Antioxidantes/farmacología , Clorofila A , Cianobacterias/efectos de los fármacos , Cianobacterias/genética , Reparación del ADN/efectos de la radiación , Clima Desértico , Peroxidación de Lípido/efectos de la radiación , Viabilidad Microbiana/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Primary closure following laparoscopic common bile duct exploration (LCBDE) has been widely adopted because of the efficacy and safety in treatment of common bile duct (CBD) stones. However, the risk factors for bile leakage, the most common complication after primary closure, has not been clarified yet. METHODS: A retrospective cohort study of patients who underwent LCBDE with primary closure after choledochotomy between Feb. 2012 and Jun. 2016 was performed. Risk factors for bile leakage were identified by logistic regression inculding demographic factors, preoperative condition and surgical details. RESULTS: Between Feb. 2012 and Jun. 2016, a total of 265 LCBDE procedures were applied in our hospital and 141 patients with primary closure were included in this study. Bile leakage occurred in 11.3% (16/141) of these patients, and happened more frequently in patients with slender CBD (<1 vs ≥1 cm, 31.6% vs 7.0%, p = 0.04) and those managed by inexperienced surgeons (initial 70 cases vs later cases, 17.1% vs 5.6%, p = 0.04). After multivariable regression, the diameter of CBD [OR 95% CI, 3.799 (1.081-13.349), p = 0.04] and experience of surgeons [OR 95% CI, 4.228 (1.330-13.438), p = 0.03] were significantly related to bile leakage. CONCLUSION: Slender CBD and inexperienced surgeons were the high risk factors for bile leakage after primary closure following LCBDE.
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Bilis , Procedimientos Quirúrgicos del Sistema Biliar/efectos adversos , Conducto Colédoco/cirugía , Laparoscopía/efectos adversos , Complicaciones Posoperatorias/etiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
It is reported that CLU rs2279590 polymorphism is significantly associated with Alzheimer's disease (AD) in European ancestry. Recent studies investigated rs2279590 polymorphism in Asian population (Chinese, Japanese and Korean). Four studies showed negative association and two studies showed weak association between rs2279590 and AD. We believe that the weak association or no association may be caused by the relatively small sample size in Asian population. Here, we reinvestigated the association in Asian population. Meanwhile, to investigate the genetic heterogeneity of the rs2279590 polymorphism in Asian and Caucasian populations, we searched the PubMed and AlzGene databases and selected 11 independent studies (6 studies in Asian population and 5 studies in Caucasian population) including 20,655 individuals (8,605 cases and 12,050 controls) for meta-analysis. Our results showed significant association between rs2279590 polymorphism and AD in Asian population with P = 2.00E-04 and P = 2.00E-04 using additive and recessive models, respectively. We observed no significant heterogeneity between Asian and Caucasian populations. We believe that our results may be helpful to understand the mechanisms of CLU in AD pathogenesis and will be useful for future genetic studies in AD.
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Enfermedad de Alzheimer/genética , Clusterina/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Enfermedad de Alzheimer/etnología , Pueblo Asiatico , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Humanos , Masculino , Modelos Genéticos , Oportunidad Relativa , PubMed/estadística & datos numéricos , Sensibilidad y Especificidad , Población BlancaRESUMEN
As ubiquitous molecular chaperones, small heat shock proteins (sHSPs) are crucial for protein homeostasis. It is not clear why sHSPs are able to bind a wide spectrum of non-native substrate proteins and how such binding is enhanced by heat shock. Here, by utilizing a genetically incorporated photo-cross-linker (p-benzoyl-l-phenylalanine), we systematically characterized the substrate-binding residues in IbpB (a sHSP from Escherichia coli) in living cells over a wide spectrum of temperatures (from 20 to 50 °C). A total of 20 and 48 residues were identified at normal and heat shock temperatures, respectively. They are not necessarily hydrophobic and can be classified into three types: types I and II were activated at low and normal temperatures, respectively, and type III mediated oligomerization at low temperature but switched to substrate binding at heat shock temperature. In addition, substrate binding of IbpB in living cells began at temperatures as low as 25 °C and was further enhanced upon temperature elevation. Together, these in vivo data provide novel structural insights into the wide substrate spectrum of sHSPs and suggest that sHSP is able to hierarchically activate its multi-type substrate-binding residues and thus act as a robust chaperone in cells under fluctuating growth conditions.
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Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Proteínas de Choque Térmico/metabolismo , Respuesta al Choque Térmico/fisiología , Multimerización de Proteína/fisiología , Sitios de Unión , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Choque Térmico/genética , Calor , Mapeo Peptídico/métodosRESUMEN
OBJECTIVE: This study was conducted to investigate the role of stromal-derived factor-1 alpha (SDF-1α) in a secondary brain injury after traumatic brain injury (TBI) in rats, and to further elucidate its underlying regulatory mechanisms. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent TBI for 30 min, and then received intracranial injections of recombinant SDF-1α, SDF-1α antibody, or saline as a vehicle control. At 24 h after TBI, brain tissues from the experimental animals were subjected to histology, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and western blot analyses. RESULTS: TBI-induced brain edema and blood-brain barrier disruption were ameliorated by post-injury injections of SDF-1α. TBI-induced neuronal degradation and apoptosis, accompanied by increased cleaved caspase-3, cleaved PARP and Bax, and decreased Bcl-2 were found to be attenuated by SDF-1α injection. Nitric oxide (NO) and inducible nitric oxide synthase (iNOS) levels decreased in SDF-1α treated animals after TBI. SDF-1α repressed inflammatory responses by inhibiting the expression of pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. However, neutralizing the effect of SDF-1α with its antibody abolished these therapeutic alterations in TBI animals. Importantly, SDF-1α attenuated the brain lesion by affecting the ERK and NF-κB signaling pathways after mechanical head trauma in rats. CONCLUSIONS: SDF-1α ameliorates mechanical trauma-induced pathological changes via its anti-apoptotic and anti-inflammatory action in the brain.
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Antiinflamatorios/uso terapéutico , Lesiones Encefálicas/tratamiento farmacológico , Quimiocina CXCL12/uso terapéutico , Animales , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Edema Encefálico/patología , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Quimiocina CXCL12/farmacología , Citocinas/genética , Citocinas/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
Landscape evolution has profound effects on ecosystems. Recently, some studies suggest that China has implemented plans leading in the greening of the world by mainly describing the changes based on satellite data. However, few studies have analyzed the policy effect on ecosystem improvement from the perspective of landscape pattern evolution. Among the numerous ecological policy plans, China's key ecological function zones plan is an important one. In this study, we focus on depicting the long-term and large-scale landscape evolution in China's key ecological function zones, which are accounting for 40.2% of China's land area, and include four-type ecoregions where ecosystems are fragile or important, to comprehensively explore the environmental influences of policy planning. For this purpose, we first described the landscape composition changes and conversion mechanisms in China's key ecological function zones from 1990 to 2015. Then we captured the detailed pattern evolution characteristics by landscape indices. The results show that these ecoregions were mostly evolving in an unfavorable direction in these 25 years, i.e. destruction of habitats and increment of fragmentation. Although greening areas increased based on other recent researches, the landscape pattern became worse, indicating it is necessary for the detailed analysis of landscape ecology and more accurate ecological planning. We also found the deterioration of the ecological environment had been uncharacteristically stopped or even improved in wind prevention and sand fixation ecoregions and biodiversity maintenance ecoregions after the implementation of this plan. Furthermore, we assumed that the policy is more prominent in these prohibiting sabotages and protecting areas with fragile ecological bases, which may be caused by the differentiated transfer payments in different ecoregions. Finally, some planning suggestions, such as stricter land use control, the regional balance of ecological transfer payments and deepening of ecological migration policies, etc., were proposed for promoting better future environmental changes.
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Conservación de los Recursos Naturales , Ecosistema , Biodiversidad , Política Pública , ChinaRESUMEN
N6-methyladenosine (m6A) modification plays a crucial role in thyroid carcinoma (THCA). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) is a m6A-binding protein. We aimed to explore the effect of IGF2BP2 on the development of THCA. Differentially expressed genes (DEGs) were screened from GSE50901 and GSE60542 datasets. LinkedOmics, Genebank, and Sequence-based RNA Adenosine Methylation Site Predictor databases were employed to find potential m6A modification sites. Protein-protein interaction network and receiver-operating characteristic curves were applied to determine hub genes of THCA. ESTIMATE revealed the effect of IGF2BP2 on tumor immunity. The mRNA expression of IGF2BP2 was detected using real-time quantitative polymerase chain reaction. The viability, migration, and invasion were assessed by Cell Counting Kit-8, wound healing, and transwell assays. A total of 166 common DEGs were identified from GSE50901 and GSE60542 datasets. One m6A-related gene, IGF2BP2, was differentially expressed in THCA and selected as the research target. The hub genes (CD44, DCN, CXCL12, ICAM1, SDC4, KIT, CTGF, and FMOD) were identified with high prediction values for THCA. Subsequently, the target genes of IGF2BP2, SDC4, and ICAM1, which had potential m6A modification sites, were screened out based on the hub genes. IGF2BP2 was upregulated in THCA and IGF2BP2 expression was positively correlated with immune infiltration in THCA. Additionally, knockdown of IGF2BP2 inhibited the proliferation, invasion, and migration of THCA cells. IGF2BP2 has a contributory effect on the progression of THCA, which is a novel biomarker and a therapeutic target for THCA.
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Biología Computacional , Regulación Neoplásica de la Expresión Génica , Mapas de Interacción de Proteínas , Proteínas de Unión al ARN , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Movimiento Celular , Línea Celular Tumoral , Proliferación Celular , Bases de Datos Genéticas , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
BACKGROUND: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy.
Asunto(s)
Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias del Sistema Digestivo/inmunología , Neoplasias del Sistema Digestivo/metabolismo , Animales , Reprogramación MetabólicaRESUMEN
Carfilzomib, a second-generation proteasome inhibitor, has been approved as a treatment for relapsed and/or refractory multiple myeloma. Nevertheless, the molecular mechanism by which Carfilzomib inhibits esophageal squamous cell carcinoma (ESCC) progression largely remains to be determined. In the present study, we found that Carfilzomib demonstrated potent anti-tumor activity against esophageal squamous cell carcinoma both in vitro and in vivo. Mechanistically, carfilzomib triggers mitochondrial apoptosis and reprograms cellular metabolism in ESCC cells. Moreover, it has been identified that activating transcription factor 3 (ATF3) plays a crucial cellular target role in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively antagonized the effects of carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, the ATF3 protein is specifically bound to lactate dehydrogenase A (LDHA) to effectively suppress LDHA-mediated metabolic reprogramming in response to carfilzomib treatment. Research conducted in xenograft models demonstrates that ATF3 mediates the anti-tumor activity of Carfilzomib. The examination of human esophageal squamous cell carcinoma indicated that ATF3 and LDHA have the potential to function as innovative targets for therapeutic intervention in the treatment of ESCC. Our findings demonstrate the novel function of Carfilzomib in modulating ESCC metabolism and progression, highlighting the potential of Carfilzomib as a promising therapeutic agent for the treatment of ESCC.
Asunto(s)
Factor de Transcripción Activador 3 , Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Oligopéptidos , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Oligopéptidos/farmacología , Línea Celular Tumoral , Antineoplásicos/farmacología , Xenoinjertos , Trasplante de Neoplasias , Humanos , Animales , Ratones , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Apoptosis , Reprogramación Metabólica/efectos de los fármacos , Factor de Transcripción Activador 3/metabolismoRESUMEN
Human liver organoids (HLOs) differentiated from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and adult stem cells (ASCs) can recapitulate the structure and function of human fetal liver tissues, thus being considered as a promising tissue model for liver diseases and predictive compound screening. However, the adoption of HLOs in drug discovery faces several technical challenges, which include the lengthy differentiation process with multiple culture media leading to batch-to-batch variation, short-term maintenance of hepatic functions post-maturation, low assay throughput due to Matrigel dissociation and HLO transfer to a microtiter well plate, and insufficient maturity levels compared to primary hepatocytes. To address these issues, expandable HLOs (Exp-HLOs) derived from human iPSCs were generated by optimizing differentiation protocols, which were rapidly printed on a 144-pillar plate with sidewalls and slits (144PillarPlate) and dynamically cultured for up to 20 days into differentiated HLOs (Diff-HLOs) in a 144-perfusion plate with perfusion wells and reservoirs (144PerfusionPlate) for in situ organoid culture and analysis. The dynamically cultured Diff-HLOs exhibited greater maturity and reproducibility than those cultured statically, especially after a 10-day differentiation period. In addition, Diff-HLOs in the pillar/perfusion plate were tested with acetaminophen and troglitazone for 3 days to assess drug-induced liver injury (DILI) and then incubated in an expansion medium for 10 days to evaluate liver recovery from DILI. The assessment of liver regeneration post-injury is critical to understanding the mechanism of recovery and determining the threshold drug concentration beyond which there will be a sharp decrease in the liver's regenerative capacity. We envision that bioprinted Diff-HLOs in the pillar/perfusion plate could be used for high-throughput screening (HTS) of hepatotoxic compounds due to the short-term differentiation of passage-able Exp-HLOs, stable hepatic function post-maturation, high reproducibility, and high throughput with capability of in situ organoid culture, testing, staining, imaging, and analysis. Graphical abstract: The overall process of dynamic liver organoid culture and in situ analysis in the 144PillarPlate/144PerfusionPlate for high-throughput hepatotoxicity assays.