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The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-ß expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-ß induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-ß, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-ß mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-ß via mitochondrial dsDNA release.
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Citosol , Estrés del Retículo Endoplásmico , Interferón beta , Proteínas de la Membrana , Nucleotidiltransferasas , Respuesta de Proteína Desplegada , Humanos , Animales , Ratones , Nucleotidiltransferasas/metabolismo , Citosol/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Interferón beta/metabolismo , ADN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , eIF-2 Quinasa/metabolismo , Endorribonucleasas/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Tapsigargina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Activación Transcripcional , ADN Mitocondrial/metabolismoRESUMEN
The type of muscle fiber plays a crucial role in the growth, development, and dynamic plasticity of animals' skeletal muscle. Additionally, it is a primary determinant of the quality of both fresh and processed meat. Therefore, understanding the regulatory factors that contribute to muscle fibers' heterogeneity is of paramount importance. Recent advances in sequencing and omics technologies have enabled comprehensive cross-verification of research on the factors affecting the types of muscle fiber across multiple levels, including the genome, transcriptome, proteome, and metabolome. These advancements have facilitated deeper exploration into the related biological questions. This review focused on the impact of individual characteristics, feeding patterns, and genetic regulation on the proportion and interconversion of different muscle fibers. The findings indicated that individual characteristics and feeding patterns significantly influence the type of muscle fiber, which can effectively enhance the type and distribution of muscle fibers in livestock. Furthermore, non-coding RNA, genes and signaling pathways between complicated regulatory mechanisms and interactions have a certain degree of impact on muscle fibers' heterogeneity. This, in turn, changes muscle fiber profile in living animals through genetic selection or environmental factors, and has the potential to modulate the quality of fresh meat. Collectively, we briefly reviewed the structure of skeletal muscle tissue and then attempted to review the inevitable connection between the quality of fresh meat and the type of muscle fiber, with particular attention to potential events involved in regulating muscle fibers' heterogeneity.
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Nitrite is a common nitrogen-containing compound that possesses high biological toxicity, thereby posing a serious threat to aquatic organisms. Therefore, it is imperative to develop a rapid and quantitative determination approach for nitrite. In this study, the aim was to prepare a novel electrochemical sensor to determine nitrite. This was achieved by synthesizing Au/Zn dendritic complexes on a carbon cloth self-supported electrode after plasma treated by a stepwise strategy of electrodeposition and in-situ corrosion. In accordance with the optimal experimental conditions, the electrode exhibited remarkable catalytic activity for the electrooxidation of nitrite ions (pH = 8.0), accompanied by a considerable enhancement in peak anodic current in comparison to the unmodified electrode. The sensor exhibited a wide linear range (1-833 µM, 833-8330 µM), high sensitivity (3506 µA mM-1 cm-2, 538 µA mM-1 cm-2), a low detection limit (0.43 µM), and excellent selectivity, reproducibility, and stability for the determination of nitrite. Furthermore, the prepared sensor was successfully applied to the detection of nitrite in tap water, fish holding pond water and duck pond water, demonstrating good recovery and no significant difference from the spectrophotometric results. The results suggest that the electrochemical sensor developed in this study represents a straightforward yet efficacious approach to the development of advanced portable sensors for aquaculture applications.
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Acuicultura , Carbono , Técnicas Electroquímicas , Oro , Nitritos , Contaminantes Químicos del Agua , Zinc , Nitritos/análisis , Contaminantes Químicos del Agua/análisis , Técnicas Electroquímicas/métodos , Técnicas Electroquímicas/instrumentación , Oro/química , Zinc/análisis , Electrodos , Monitoreo del Ambiente/métodosRESUMEN
Follicular atresia in chickens seriously reduced the egg production and economic benefits of chickens. LncRNA plays a key role in the process of follicular atresia. In this study, RNA-seq and Ribo-seq were performed on normal and atretic follicles of Dahen broilers to screen out lncRNAs that may regulate follicle atresia, and to study the molecular mechanisms of their regulation. GRN granulin precursor (lncGRN, ID: 101748909) was highly expressed in atretic follicles with translational ability. A molecular regulatory network of lncGRN/miR-103-3p/FBXW7 was constructed through bioinformatics analysis and dual luciferase reporting. LncGRN promoted the expression of FBXW7 by adsorption of miR-103-3p, thereby inhibiting the proliferation of chicken granulosa cells (GCs), promoting apoptosis of chicken GCs and inhibiting steroid hormone synthesis thus induced follicular atresia. Meanwhile, we also found a micropeptide named GRN-122aa derived by lncGRN which can promote follicular atresia. In conclusion, our study found that lncGRN promoted follicular atresia through the lncGRN/miR-103-3p/FBXW7 axis and the translation micropeptide GRN-122aa. This study provided new insight into the post-transcriptional regulation mechanism of lncGRN suggesting that lncGRN may act as a potential to regulate chicken follicle development, and provided a theoretical argument for further improving the egg production of chickens through molecular breeding.
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Based on polarization holography, circular polarization beam splitters with separation angles of up to 100° have been fabricated. The left- and right-handed circularly polarized waves can be reconstructed by the two holograms that were designed by the tensor theory of polarization holography, respectively. In the fabrication of circular polarization beam splitters, two holograms were recorded only by the interference method in the same area of the polarization-sensitive material. This method is simple, inexpensive, and easy to adjust the separation angles and element size. The diffraction efficiency and the polarization state of the reconstructed waves were tested under different incident waves, and the experimental results are in good agreement with the theory. This work not only deepens our understanding of polarization holography but also expands the applications of polarization holography.
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Acid-modified biochar is a modified biochar material with convenient preparation, high specific surface area, and rich pore structure. It has great potential for application in the heavy metal remediation, soil amendments, and carrying catalysts. Specific surface area (SSA), average pore size (APS), and total pore volume (TPV) are the key properties that determine its adsorption capacity, reactivity, and water holding capacity, and an intensive study of these properties is essential to optimize the performance of biochar. But the complex interactions among the preparation conditions obstruct finding the optimal modification strategy. This study collected dataset through bibliometric analysis and used four typical machine learning models to predict the SSA, APS, and TPV of acid-modified biochar. The results showed that the extreme gradient boosting (XGB) was optimal for the test results (SSA R2 = 0.92, APS R2 = 0.87, TPV R2 = 0.96). The model interpretation revealed that the modification conditions were the major factors affecting SSA and TPV, and the pyrolysis conditions were the major factors affecting APS. Based on the XGB model, the modification conditions of biochar were optimized, which revealed the ideal preparation conditions for producing the optimal biochar (SSA = 727.02 m2/g, APS = 5.34 nm, TPV = 0.68 cm3/g). Moreover, the biochar produced under specific conditions verified the generalization ability of the XGB model (R2 = 0.99, RMSE = 12.355). This study provides guidance for optimizing the preparation strategy of acid-modified biochar and promotes its potentiality for industrial application.
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Carbón Orgánico , Aprendizaje Automático , Carbón Orgánico/química , Bibliometría , Porosidad , AdsorciónRESUMEN
Control of meat quality traits is an important goal of any farm animal production, including poultry. A better understanding of the biochemical properties of muscle fiber properties that drive muscle development and ultimately meat quality constitutes one of the major challenging topics in animal production and meat science. In this paper, the existing classification methods of skeletal muscle fibers in poultry were reviewed and the relationship between contractile and metabolic characteristics of muscle fibers and poultry meat quality was described. Finally, a comprehensive review of multiple potential factors affecting muscle fiber distribution and conversion is presented, including breed, sex, hormones, growth performance, diet, muscle position, exercise, and ambient temperature. We emphasize that knowledge of muscle fiber typing is essential to better understand how to control muscle characteristics throughout the life cycle of animals to better manage the final quality of poultry meat.
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Carne , Fibras Musculares Esqueléticas , Aves de Corral , Animales , Fibras Musculares Esqueléticas/fisiología , Fibras Musculares Esqueléticas/metabolismo , Carne/análisis , Aves de Corral/fisiología , Pollos/fisiología , Crianza de Animales Domésticos/métodosRESUMEN
Babesia is a tick-transmitted parasite that infects wild and domestic animals, causes babesiosis in humans, and is an increasing public health concern. Here, we investigated the prevalence and molecular characteristics of Babesia infections in the rodents in Southeastern Shanxi, China. Small rodents were captured, and the liver and spleen tissues were used for Babesia detection using traditional PCR and sequencing of the partial 18S rRNA gene. The analysis revealed that 27 of 252 small rodents were positive for Babesia, with an infection rate of 10.71%. The infection rates in different sexes and rodent tissues were not statistically different, but those in different rodent species, habitats, and sampling sites were statistically different. The highest risk of Babesia infection was observed in Niviventer confucianus captured from the forests in Huguan County. Forty-three sequences from 27 small rodents positive for Babesia infection were identified as Babesia microti, including 42 sequences from 26 N. confucianus, and one sequence from Apodemus agrarius. Phylogenetic analysis showed that all sequences were clustered together and had the closest genetic relationship with Babesia microti strains isolated from Rattus losea and N. confucianus in China, and belonged to the Kobe-type, which is pathogenic to humans. Compared to other Kobe-type strains based on the nearly complete 18S rRNA gene, the sequences obtained in this study showed the difference by 1-3 bp. Overall, a high prevalence of Babesia microti infection was observed in small rodents in Southeastern Shanxi, China, which could benefit us to take the implementation of relevant prevention and control measures in this area.
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Babesia microti , Babesiosis , Filogenia , ARN Ribosómico 18S , Roedores , Animales , Babesia microti/genética , Babesia microti/aislamiento & purificación , China/epidemiología , Babesiosis/epidemiología , Babesiosis/parasitología , Prevalencia , Roedores/parasitología , ARN Ribosómico 18S/genética , Femenino , Masculino , Enfermedades de los Roedores/epidemiología , Enfermedades de los Roedores/parasitologíaRESUMEN
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious and common extra-articular disease manifestation. Patients with RA-ILD experience reduced bacterial diversity and gut bacteriome alterations. However, the gut mycobiome and virome in these patients have been largely neglected. In this study, we performed whole-metagenome shotgun sequencing on fecal samples from 30 patients with RA-ILD, and 30 with RA-non-ILD, and 40 matched healthy controls. The gut bacteriome and mycobiome were explored using a reference-based approach, while the gut virome was profiled based on a nonredundant viral operational taxonomic unit (vOTU) catalog. The results revealed significant alterations in the gut microbiomes of both RA-ILD and RA-non-ILD groups compared with healthy controls. These alterations encompassed changes in the relative abundances of 351 bacterial species, 65 fungal species, and 4,367 vOTUs. Bacteria such as Bifidobacterium longum, Dorea formicigenerans, and Collinsella aerofaciens were enriched in both patient groups. Ruminococcus gnavus (RA-ILD), Gemmiger formicilis, and Ruminococcus bromii (RA-non-ILD) were uniquely enriched. Conversely, Faecalibacterium prausnitzii, Bacteroides spp., and Roseburia inulinivorans showed depletion in both patient groups. Mycobiome analysis revealed depletion of certain fungi, including Saccharomyces cerevisiae and Candida albicans, in patients with RA compared with healthy subjects. Notably, gut virome alterations were characterized by an increase in Siphoviridae and a decrease in Myoviridae, Microviridae, and Autographiviridae in both patient groups. Hence, multikingdom gut microbial signatures showed promise as diagnostic indicators for both RA-ILD and RA-non-ILD. Overall, this study provides comprehensive insights into the fecal virome, bacteriome, and mycobiome landscapes of RA-ILD and RA-non-ILD gut microbiota, thereby offering potential biomarkers for further mechanistic and clinical research.
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Artritis Reumatoide , Bacterias , Heces , Microbioma Gastrointestinal , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/microbiología , Enfermedades Pulmonares Intersticiales/virología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/microbiología , Heces/microbiología , Heces/virología , Femenino , Masculino , Persona de Mediana Edad , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Anciano , Viroma , Micobioma , Adulto , Virus/clasificación , Virus/aislamiento & purificación , Virus/genética , Hongos/aislamiento & purificación , Hongos/clasificaciónRESUMEN
Objective:To compare the expression levels of SCCAg in inverted papilloma of the nasal sinuses and other sinuses and sinus masses. To investigate the correlation between the expression of SCCAg in sinonasal inverted papilloma and outcome. Methods:Sixty-eight patients with unilateral nasal and sinus masses admitted to the Otorhinolaryngology Center of the Affiliated Hospital of Guangdong Medical University from September 2020 to February 2023 were randomly selected, including 31 patients with inverted papilloma ï¼experimental groupï¼ and 37 patients with unilateral nasal and sinus masses excluding inverted papilloma ï¼control groupï¼. The application of automatic chemiluminescence immunoassay to test the serum SCCAg of the experimental group before surgery and 1 week after surgery, and the control group to measure the serum SCCAg before surgery. Clinical data were also collected. Results:There was no significant difference between the experimental group and the control group in gender and preoperative peripheral blood inflammatory indicators. However, there was significant difference in age and preoperative serum SCCAg levelï¼P<0.001ï¼. The serum SCCAg levels of the experimental group before and 1 week after surgery were significantly differentï¼P<0.001ï¼. The positive predictive value, negative predictive value, sensitivity and specificity of serum SCCAg in the diagnosis of varus papilloma were 92.6%, 85.4%, 77.4%, 94.6% and 0.72, respectively. The effect of serum SCCAg in the diagnosis of varus papilloma was analyzed by drawing the subject's working characteristic curve, and the area under the curve was 0.968ï¼P<0.001ï¼. When serum SCCAg greater than 2.7 ng/mL, the sensitivity and specificity were 67.7% and 94.6%, respectively. There was statistical significance in serum SCCAg levels between patients with and without recurrenceï¼P<0.05ï¼. Conclusion:The level of SCCAg in unilateral nasal and sinuses tumors, excluding squamous cell carcinoma, was significantly increased in inverted papilloma. The detection of serum SCCAg can be used as a simple and cost-effective auxiliary diagnostic tool for patients with nasal inverted papilloma before operation. Significant differences in preoperative and postoperative levels can be used for preliminary evaluation of surgical efficacy. Monitoring the serum SCCAg level in patients with inverted papilloma after surgery can predict recurrence and provide a simple and feasible method for postoperative follow-up.
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Antígenos de Neoplasias , Papiloma Invertido , Serpinas , Humanos , Papiloma Invertido/sangre , Masculino , Femenino , Serpinas/sangre , Persona de Mediana Edad , Antígenos de Neoplasias/sangre , Neoplasias de los Senos Paranasales/sangre , Adulto , Neoplasias Nasales/sangre , Relevancia ClínicaRESUMEN
Optimization techniques play a pivotal role in advancing drug development, serving as the foundation of numerous generative methods tailored to efficiently design optimized molecules derived from existing lead compounds. However, existing methods often encounter difficulties in generating diverse, novel, and high-property molecules that simultaneously optimize multiple drug properties. To overcome this bottleneck, we propose a multiobjective molecule optimization framework (MOMO). MOMO employs a specially designed Pareto-based multiproperty evaluation strategy at the molecular sequence level to guide the evolutionary search in an implicit chemical space. A comparative analysis of MOMO with five state-of-the-art methods across two benchmark multiproperty molecule optimization tasks reveals that MOMO markedly outperforms them in terms of diversity, novelty, and optimized properties. The practical applicability of MOMO in drug discovery has also been validated on four challenging tasks in the real-world discovery problem. These results suggest that MOMO can provide a useful tool to facilitate molecule optimization problems with multiple properties.
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Descubrimiento de Drogas , Descubrimiento de Drogas/métodos , Diseño de Fármacos , AlgoritmosRESUMEN
BACKGROUND: Accidental impact on a player's head by a powerful soccer ball may lead to brain injuries and concussions during games. It is crucial to assess these injuries promptly and accurately on the field. However, it is challenging for referees, coaches, and even players themselves to accurately recognize potential injuries and concussions following such impacts. Therefore, it is necessary to establish a list of minimum ball velocity thresholds that can result in concussions at different impact locations on the head. Additionally, it is important to identify the affected brain regions responsible for impairments in brain function and potential clinical symptoms. METHODS: By using a full human finite element model, dynamic responses and brain injuries caused by unintentional soccer ball impacts on six distinct head locations (forehead, tempus, crown, occiput, face, and jaw) at varying ball velocities (10, 15, 20, 25, 30, 35, 40, and 60 m/s) were simulated and investigated. Intracranial pressure, Von-Mises stress, and first principal strain were analyzed, the ball velocity thresholds resulting in concussions at different impact locations were evaluated, and the damage evolution patterns in the brain tissue were analyzed. RESULTS: The impact on the occiput is most susceptible to induce brain injuries compared to all other impact locations. For a conservative assessment, the risk of concussion is present once the soccer ball reaches 17.2 m/s in a frontal impact, 16.6 m/s in a parietal impact, 14.0 m/s in an occipital impact, 17.8 m/s in a temporal impact, 18.5 m/s in a facial impact or 19.2 m/s in a mandibular impact. The brain exhibits the most significant dynamic responses during the initial 10-20 ms, and the damaged regions are primarily concentrated in the medial temporal lobe and the corpus callosum, potentially causing impairments in brain functions. CONCLUSIONS: This work offers a framework for quantitatively assessing brain injuries and concussions induced by an unintentional soccer ball impact. Determining the ball velocity thresholds at various impact locations provides a benchmark for evaluating the risks of concussion. The examination of brain tissue damage evolution introduces a novel approach to linking biomechanical responses with possible clinical symptoms.
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Conmoción Encefálica , Fútbol , Humanos , Fútbol/lesiones , Conmoción Encefálica/fisiopatología , Fenómenos Biomecánicos , Análisis de Elementos Finitos , Lesiones Encefálicas/fisiopatología , Traumatismos en Atletas/fisiopatología , Simulación por Computador , Encéfalo/fisiopatología , Aceleración , Presión Intracraneal/fisiologíaRESUMEN
Drug synergy therapy is a promising strategy for cancer treatment. However, the extensive variety of available drugs and the time-intensive process of determining effective drug combinations through clinical trials pose significant challenges. It requires a reliable method for the rapid and precise selection of drug synergies. In response, various computational strategies have been developed for predicting drug synergies, yet the exploitation of heterogeneous biological network features remains underexplored. In this study, we construct a heterogeneous graph that encompasses diverse biological entities and interactions, utilizing rich data sets from sources, such as DrugCombDB, PubChem, UniProt, and cancer cell line encyclopedia (CCLE). We initialize node feature representations and introduce a novel virtual node to enhance drug representation. Our proposed method, the heterogeneous graph attention network for drug-drug synergy prediction (HANSynergy), has been experimentally validated to demonstrate that the heterogeneous graph attention network can extract key node features, efficiently harness the diversity of information, and further enhance network functionality through the incorporation of a multihead attention mechanism. In the comparative experiment, the highest accuracy (Acc) and area under the curve (AUC) are 0.877 and 0.947, respectively, in DrugCombDB_early data set, demonstrating the superiority of HANSynergy over the competing methods. Moreover, protein-protein interactions are important in understanding the mechanism of action of drugs. The heterogeneous attention mechanism facilitates protein-protein interaction analysis. By analyzing the changes of attention weight before and after heterogeneous network training, we investigated proteins that may be associated with drug combinations. Additionally, case studies align our findings with existing research, underscoring the potential of HANSynergy in drug synergy prediction. This advancement not only contributes to the burgeoning field of drug synergy prediction but also holds the potential to provide valuable insights and uncover new drug synergies for combating cancer.
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Sinergismo Farmacológico , Humanos , Bases de Datos Farmacéuticas , Antineoplásicos/farmacología , Antineoplásicos/química , Biología Computacional/métodosRESUMEN
A Cu2O-catalyzed cascade phosphinylation/cyclization reaction of 2'-aminochalcones and diphenylphosphine oxides to produce hemi-indigo derivatives has been developed. This strategy facilitates the sequential formation of a C-P bonds and a C-N bond in a single reaction step. Notably, the approach features one-pot operation, an earth-abundant copper catalyst, readily available starting materials, a broad substrate scope and high compatibility with functional groups, providing 33 compounds in acceptable yields.
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Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.
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Flavonoides , Glucólisis , Neoplasias Ováricas , Propiofenonas , Proteínas Quinasas Asociadas a Fase-S , Ubiquitinación , Propiofenonas/farmacología , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Flavonoides/farmacología , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Glucólisis/efectos de los fármacos , Animales , Transducción de Señal/efectos de los fármacos , Cadherinas/metabolismo , Carcinogénesis/efectos de los fármacos , Antígenos CD/metabolismo , Hexoquinasa/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Fitoterapia , Ratones Desnudos , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-ß expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-ß induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-ß, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-ß mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-ß via mitochondrial dsDNA release.
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The lipogenesis and steroidogenesis of granulosa cells are crucial during follicular development, yet it remains unclear whether dual-specificity phosphatase 8 (DUSP8) is involved. In this study, the specific role of DUSP8 in lipogenesis and steroidogenesis was investigated through culturing chicken granulosa cells in vitro. The results revealed that the expression levels of adipogenic genes were elevated after DUSP8 overexpression and reduced after knockdown. The same was observed for lipid deposition in granulosa cells. Meanwhile, the steroidogenic gene expression and progesterone synthesis were promoted after DUSP8 overexpression and inhibited after knockdown. In addition, we also found that DUSP8 blocked the phosphorylation of extracellular regulatory kinase 1/2 (ERK1/2). Based on the previous results that activated ERK1/2 signaling inhibited lipid deposition and progesterone synthesis in chicken granulosa cells, we demonstrated that DUSP8 promoted lipid deposition and progesterone synthesis through mediating the ERK1/2 signaling pathway. The results will improve our understanding of the molecular regulatory mechanisms regarding lipid metabolism and progesterone synthesis in chicken granulosa cells.
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Pollos , Células de la Granulosa , Lipogénesis , Sistema de Señalización de MAP Quinasas , Animales , Femenino , Células Cultivadas , Pollos/metabolismo , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Regulación de la Expresión Génica , Células de la Granulosa/metabolismo , Progesterona/biosíntesis , Progesterona/metabolismoRESUMEN
OBJECTIVE: 1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. METHODS: Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. RESULTS: Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. CONCLUSIONS: When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Cromosomas Humanos Par 1 , Lenalidomida , Mieloma Múltiple , Humanos , Bortezomib/administración & dosificación , Lenalidomida/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/genética , Femenino , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Anciano , Cromosomas Humanos Par 1/genética , Adulto , Estudios Retrospectivos , Pronóstico , Resultado del Tratamiento , Aberraciones Cromosómicas , Anciano de 80 o más Años , Dexametasona/administración & dosificaciónRESUMEN
Long noncoding RNAs (lncRNA) are a class of non-coding RNAs greater than 200 bp in length with limited peptide-coding function. The transcription of LINC00152 is derived from chromosome 2p11.2. Many studies prove that LINC00152 influences the progression of various tumors via promoting the tumor cells malignant phenotype, chemoresistance, and immune escape. LINC00152 is regulated by multiple transcription factors and DNA hypomethylation. In addition, LINC00152 participates in the regulation of complex molecular signaling networks through epigenetic regulation, protein interactions, and competitive endogenous RNA (ceRNA). Here, we provide a systematic review of the upstream regulatory factors of LINC00152 expression level in different types of tumors. In addition, we revisit the main functions and mechanisms of LINC00152 as driver oncogene and biomarker in pan-cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Methods > RNA Analyses in Cells RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
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Neoplasias , Oncogenes , ARN Largo no Codificante , Humanos , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Oncogenes/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Three-dimensional (3D) graphene oxide (GO)-based aerogels, GO and 4-methyl-5-thiazoleethanol (MTZE) composites, were prepared by a facile hydrothermal method. Due to the hydrogen bonding and π-π stacking interactions, the produced 3D GO-MTZE composites possessed large cylindrical structures. The morphologies, composition, and chemical states of 3D GO-MTZE3:1 composite were characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and N2 adsorption-desorption isotherms based on the Brunauer-Emmett-Teller (BET) method. The existence of nitrogen (N)-containing heterocyclic system and oxygen (O)-containing branched chain of MTZE contributed to the formation of 3D structures, while the complexation effect of heterocyclic sulfur (S)- and N-containing functional groups of MTZE for metal cations dominated the adsorption performance of 3D GO-MTZE3:1 composite, which could selectively adsorb copper ions (Cu2+). In addition, the better hydrophobic property of 3D GO-MTZE3:1 composite facilitates its facile recycling from aqueous solution after adsorption. The adsorption data of 3D GO-MTZE3:1 composite toward Cu2+ fitted well (R2 = 0.9996) with the linear pseudo-second-order kinetic model, giving an equilibrium rate constant (k2) of 0.0187 g mg-1 min-1. The linear Langmuir isothermal model could more accurately describe the experimental data, indicating the adsorption process is mainly dominated by the complexation interactions between MTZE and Cu2+. The thermodynamic parameters of ΔG° (< 0), ΔH° (> 0), and ΔS° (> 0) further indicate that the adsorption is a spontaneous and endothermic, confirming that the complexation between Cu2+ and 3D GO-MTZE3:1 composite occurs. Due to its high selectivity for Cu2+, good hydrophobicity, and excellent stability, the developed 3D GO-MTZE3:1 composite possesses might be promisingly used in the aqueous selective enrichment/removal of Cu2+.