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Skeletal muscle is heterogeneous tissue, composed of fast-twitch fibers primarily relying on glycolysis and slow-twitch fibers primarily relying on oxidative phosphorylation. The relative expression and balance of glycolysis and oxidative phosphorylation in skeletal muscle are crucial for muscle growth and skeletal muscle metabolism. Here, we employed multi-omics approaches including transcriptomics, proteomics, phosphoproteomics, and metabolomics to unravel the role of circMYLK4, a differentially expressed circRNA in fast and slow-twitch muscle fibers, in muscle fiber metabolism. We discovered that circMYLK4 inhibits glycolysis and promotes mitochondrial oxidative phosphorylation. Mechanistically, circMYLK4 interacts with the voltage-gated calcium channel auxiliary subunit CACNA2D2, leading to the inhibition of Ca2+ release from the sarcoplasmic reticulum. The decrease in cytoplasmic Ca2+ concentration inhibits the expression of key enzymes, PHKB and PHKG1, involved in glycogen breakdown, thereby suppressing glycolysis. On the other hand, the increased fatty acid ß-oxidation enhances the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation. In general, circMYLK4 plays an indispensable role in maintaining the metabolic homeostasis of skeletal muscle.
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Glucólisis , Fosforilación Oxidativa , Animales , Ratones , Metabolismo Energético , Canales de Calcio/metabolismo , Canales de Calcio/genética , Músculo Esquelético/metabolismo , Humanos , Calcio/metabolismo , MasculinoRESUMEN
Type 2 diabetes mellitus (T2DM) can lead to multiple complications. T2DM-related bone damage has been linked to abnormal bone turnover, but it cannot fully explain the mechanisms of T2DM bone disease. This study attempts to elucidate the underlying mechanisms of poor bone quality in T2DM. Hence, T2DM model was induced by a high-fat diet combined with a single streptozotocin injection in 7-week-old male SD rats. Osteoblasts derived from SD rats were cultured in high glucose to mimic hyperglycemia. Low bone turnover was observed in T2DM bone with elevated levels of advanced glycation end-products (AGEs) and receptor for AGEs (RAGE). Additionally, higher levels of oxidative stress and inflammatory factors were found in T2DM bone. AGEs content in bone was pairwise correlated with RAGE, hydrogen peroxide, and inflammatory factors. Serum levels of RAGE, oxidative stress, and inflammatory factors were higher in T2DM, while AGEs content tended to be lower. Besides, 35 differentially expressed metabolites were screened in T2DM serum. Osteoblasts exposed to high glucose displayed analogous abnormal changes in these biomarkers. Thus, low bone turnover in T2DM might be partially due to excess oxidative stress and inflammation induced by AGE-RAGE signaling. Furthermore, these biomarker levels in serum were mostly consistent with bone, demonstrating their possibility for predicting bone quality in T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Productos Finales de Glicación Avanzada , Inflamación , Estrés Oxidativo , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada , Animales , Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Ratas , Inflamación/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Experimental/metabolismo , Osteoblastos/metabolismo , Remodelación ÓseaRESUMEN
BACKGROUND: Variants in the RPGR are the leading cause of X-linked retinopathies (XLRPs). Further in-depth investigation is needed to understand the natural history. METHODS: Review of all case records, molecular genetic testing results, best-corrected visual acuity (BCVA), retinal imaging data (including fundus autofluorescence imaging and optical coherence tomography (OCT)), static visual field (VF) assessments and full-field electroretinogram. RESULTS: Genetic testing was conducted on 104 male patients from 89 family pedigrees, identifying 22 novel variants and 1 de novo variant. The initial symptoms appeared in 78.2% of patients at a median age of 5 years. BCVA declined at a mean rate of 0.02 (IQR, 0-0.04) logarithm of the minimum angle of resolution per year, with a gradual, non-linear decrease over the first 40 years. Autofluorescence imaging revealed macular atrophy at a median age of 36.1 (IQR, 29.9-43.2) years. Patients experienced blindness at a median age of 42.5 (IQR, 32.9-45.2) years according to WHO visual impairment categories. OCT analysis showed a mean ellipsoid zone narrowing rate of 23.3 (IQR, -1.04-22.29) µm/month, with an accelerated reduction in the first 40 years (p<0.01). The median age at which ERG no longer detected a waveform was 26.5 (IQR, 20.5-32.8) years. Comparison by variant location indicated faster progression in patients with exon 1-14 variants during the initial two decades, while those with ORF15 variants showed accelerated progression from the third decade. CONCLUSIONS: We provide a foundation for determining the treatment window and an objective basis for evaluating the therapeutic efficacy of gene therapy for XLRP.
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Genetic germline variants of PPP2R5D (encoding: phosphoprotein phosphatase 2 regulatory protein 5D) result in PPP2R5D-related disorder (Jordan's Syndrome), which is characterized by intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder, and delayed motor skill development. The disorder originates from de novo single nucleotide mutations, generating missense variants that act in a dominant manner. Pathogenic mutations altering 13 different amino acids have been identified, with the E198K variant accounting for â¼40% of reported cases. However, the generation of a heterozygous E198K variant cell line to study the molecular effects of the pathogenic mutation has been challenging. Here, we use CRISPR-PRIME genomic editing to introduce a transition (c.592G>A) in a single PPP2R5D allele in HEK293 cells, generating E198K-heterozygous lines to complement existing E420K variant lines. We generate global protein and phosphorylation profiles of WT, E198K, and E420K cell lines and find unique and shared changes between variants and WT cells in kinase- and phosphatase-controlled signaling cascades. We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity. Treatment with rapamycin or an RPS6-kinase inhibitor (LY2584702) suppressed RPS6 phosphorylation in both, suggesting upstream activation of mTORC1/p70S6K. Intriguingly, our data suggests ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K variant. Thus, although upstream activation of mTORC1 differs between PPP2R5D-related disorder genotypes, inhibition of mTORC1 or RPS6 kinases warrants further investigation as potential therapeutic strategies for patients.
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Anomalías Múltiples , Humanos , Trastorno del Espectro Autista , Células HEK293 , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Fosforilación , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Proteómica , Proteína S6 Ribosómica/genética , Proteína S6 Ribosómica/metabolismo , Anomalías Múltiples/metabolismo , Anomalías Múltiples/patologíaRESUMEN
BACKGROUND: Skeletal muscle is composed of muscle fibers with different physiological characteristics, which plays an important role in regulating skeletal muscle metabolism, movement and body homeostasis. The type of skeletal muscle fiber directly affects meat quality. However, the transcriptome and gene interactions between different types of muscle fibers are not well understood. RESULTS: In this paper, we selected 180-days-old Large White pigs and found that longissimus dorsi (LD) muscle was dominated by fast-fermenting myofibrils and soleus (SOL) muscle was dominated by slow-oxidizing myofibrils by frozen sections and related mRNA and protein assays. Here, we selected LD muscle and SOL muscle for transcriptomic sequencing, and identified 312 differentially expressed mRNA (DEmRs), 30 differentially expressed miRNA (DEmiRs), 183 differentially expressed lncRNA (DElRs), and 3417 differentially expressed circRNA (DEcRs). The ceRNA network included ssc-miR-378, ssc-miR-378b-3p, ssc-miR-24-3p, XR_308817, XR_308823, SMIM8, MAVS and FOS as multiple core nodes that play important roles in muscle development. Moreover, we found that different members of the miR-10 family expressed differently in oxidized and glycolytic muscle fibers, among which miR-10a-5p was highly expressed in glycolytic muscle fibers (LD) and could target MYBPH gene mRNA. Therefore, we speculate that miR-10a-5p may be involved in the transformation of muscle fiber types by targeting the MYHBP gene. In addition, PPI analysis of differentially expressed mRNA genes showed that ACTC1, ACTG2 and ACTN2 gene had the highest node degree, suggesting that this gene may play a key role in the regulatory network of muscle fiber type determination. CONCLUSIONS: We can conclude that these genes play a key role in regulating muscle fiber type transformation. Our study provides transcriptomic profiles and ceRNA interaction networks for different muscle fiber types in pigs, providing reference for the transformation of pig muscle fiber types and the improvement of meat quality.
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Redes Reguladoras de Genes , Animales , Porcinos , MicroARNs/genética , MicroARNs/metabolismo , Perfilación de la Expresión Génica , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Transcriptoma , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Catalytic π-arene activation is based on catalysts that allow for arene exchange. To date, cyclopentadiene (Cp)-derived catalysts are the most commonly used in π-arene activation despite their low arene exchange rates. Herein, we report the synthesis, analysis, and catalytic application of Ru(II) complexes supported by phenoxo ligands, which are isolobal alternatives to Cp. The phenoxo complexes exhibit arene exchange rates significantly faster than those of the corresponding Cp complexes. The rate can be further increased through the choice of appropriate counterions. The mechanism of the arene exchange process is elucidated by kinetic and computational analyses. We demonstrate the utility of the new catalysts through an SNAr reaction between fluorobenzene and alcohols, including secondary alcohols that could not be used previously in related reactions. Moreover, the catalytic thermal decarboxylation of phenylacetic acids is presented.
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A strain engineering strategy is crucial for designing a high-performance catalyst. However, how to control the strain in metastable phase two-dimensional (2D) materials is technically challenging due to their nanoscale sizes. Here, we report that cerium dioxide (CeO2) is an ideal loading material for tuning the in-plane strain in 2D metastable 1T-phase IrO2 (1T-IrO2) via an in situ growth method. Surprisingly, 5% CeO2 loaded 1T-IrO2 with 8% compressive strain achieves an overpotential of 194 mV at 10 mA cm-2 in a three-electrode system. It also retained a high current density of 900 mA cm-2 at a cell voltage of 1.8 V for a 400 h stability test in the proton-exchange membrane device. More importantly, the Fourier transform infrared measurements and density functional theory calculation reveal that the CeO2 induced strained 1T-IrO2 directly undergo the *O-*O radical coupling mechanism for O2 generation, totally different from the traditional adsorbate evolution mechanism in pure 1T-IrO2. These findings illustrate the important role of strain engineering in paving up an optimal catalytic pathway in order to achieve robust electrochemical performance.
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The effective applications of electrochemiluminescence (ECL) across various fields necessitate ongoing research into novel luminophores and ECL strategies. In this study, self-luminous flower-like nanocomposites (Eu-tcbpe-MOF) were prepared by coordination self-assembly using the aggregation-induced emission material 1,1,2,2-tetrakis(4-carboxyphenyl)ethylene (H4TCBPE) and Eu(III) ions as the precursors. Compared with the monomers and aggregates of H4TCBPE, Eu-tcbpe-MOF exhibits stronger ECL emission. Such enhanced electrochemiluminescence is due to coordination as the coordination-triggered electrochemiluminescence (CT-ECL) enhancement effect. In this study, a cubic-structured nanocomposite (Co9S8@Au@MoS2) was used as an efficient quencher, and a more sensitive ECL detection platform was achieved by two quenching mechanisms: resonance energy transfer and competitive consumption of coreactants. N,N-Diethylethanolamine (DBAE) was used as a coreactant, and DBAE has a faster electron transfer rate and stronger energy supply efficiency than the traditional anodoluminescent coreactant tripropylamine, which effectively improves the ECL signal intensity of Eu-tcbpe-MOF. Hence, a sandwich-type ECL immunosensor was prepared by employing a dual-quenching mechanism, utilizing Eu-tcbpe-MOF as the detection probe and Co9S8@Au@MoS2 as the quencher, achieving precise detection of carcinoembryonic antigen from 0.1 pg·mL-1 to 100 ng·mL-1 with a detection limit of 35.1 fg·mL-1.
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The nanomedicine system based on dual drug delivery systems (DDDs) can significantly enhance the efficacy of tumor treatment. Herein, a metal-organic framework, Zeolite imidazole salt frames 8 (ZIF-8), was successfully utilized as a carrier to load the dual chemotherapeutic drugs doxorubicin (DOX) and camptothecin (CPT), named DOX/CPT@ZIF-8 (denoted as DCZ), and their inhibitory effects on 4T1 breast cancer cells were evaluated. The study experimentally demonstrated the synergistic effects of the dual chemotherapeutic drugs within the ZIF-8 carrier and showed that the ZIF-8 nano-carrier loaded with the dual drugs exhibited stronger cytotoxicity and inhibitory effects on 4T1 breast cancer cells compared to single-drug treatment. The use of a ZIF-8-based dual chemotherapeutic drug carrier system highlighted its potential advantages in suppressing 4T1 breast cancer cells.
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Neoplasias de la Mama , Estructuras Metalorgánicas , Nanopartículas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos , Línea Celular TumoralRESUMEN
Heterointerface engineering is presently considered a valuable strategy for enhancing the microwave absorption (MA) properties of materials via compositional modification and structural design. In this study, a sulfur-doped multi-interfacial composite (Fe7S8/NiS@C) coated with NiFe-layered double hydroxides (LDHs) is successfully prepared using a hydrothermal method and post-high-temperature vulcanization. When assembled into twisted surfaces, the NiFe-LDH nanosheets exhibit porous morphologies, improving impedance matching, and microwave scattering. Sulfur doping in composites generates heterointerfaces, numerous sulfur vacancies, and lattice defects, which facilitate the polarization process to enhance MA. Owing to the controllable heterointerface design, the unique porous structure induced multiple heterointerfaces, numerous vacancies, and defects, endowing the Fe7S8/NiS@C composite with an enhanced MA capability. In particular, the minimum reflection loss (RLmin) value reached -58.1 dB at 15.8 GHz at a thickness of 2.1 mm, and a broad effective absorption bandwidth (EAB) value of 7.3 GHz is achieved at 2.5 mm. Therefore, the Fe7S8/NiS@C composite exhibits remarkable potential as a high-efficiency MA material owing to the synergistic effects of the polarization processes, multiple scatterings, porous structures, and impedance matching.
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BACKGROUND: The use of antidepressants has increased over the years, but the relationship between antidepressant use and the risk of breast cancer is not uniform because of confounding factors. We aimed to assess the effect of antidepressants on breast cancer risk using a two-sample Mendelian randomization (MR) approach.stet METHODS: Secondary data analysis was performed on pooled data from genome-wide association studies based on single-nucleotide polymorphisms that were highly correlated with antidepressants, SSRI drugs, and serotonin and prolactin levels were selected as instrumental variables to evaluate the association between antidepressants and SSRI drugs and prolactin levels with breast cancer and ER+/ER- breast cancer. We then performed a test of the hypothesis that SSRI drugs elevate prolactin concentrations. We performed two-sample Mendelian randomization analyses using inverse variance weighting, MR-Egger regression, and weighted median methods, respectively. RESULTS: There was no significant risk association between antidepressant and SSRI use and the development of breast cancer, ER-positive or ER-negative breast cancer (P > 0.05), and serotonin concentration was not associated with breast cancer risk (P > 0.05). There was a positive causal relationship between prolactin levels and breast cancer (IVW, P = 0.02, OR = 1.058) and ER-positive breast cancer (Weighted median, P = 0.043, OR = 1.141; IVW, P = 0.009, OR = 1.125). Results in SSRI medication and prolactin levels showed no association between SSRI analogs and prolactin levels (P > 0.05). CONCLUSION: Large MR analysis showed that antidepressants as well as SSRI drugs were not associated with breast cancer risk and the SSRI-prolactin-breast cancer hypothesis did not hold in our analysis.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Análisis de la Aleatorización Mendeliana , Estudio de Asociación del Genoma Completo , Prolactina , Serotonina , Polimorfismo de Nucleótido Simple , Antidepresivos/efectos adversosRESUMEN
Serratia sp. ATCC 39006 is an important model strain for the study of prodigiosin production, whose prodigiosin biosynthesis genes (pigA-O) are arranged in an operon. Several transcription factors have been shown to control the transcription of the pig operon. However, since the regulation of prodigiosin biosynthesis is complex, the regulatory mechanism for this process has not been well established. In most γ-proteobacteria, the ROK family regulator NagC acts as a global transcription factor in response to N-acetylglucosamine (GlcNAc). In Serratia sp. ATCC 39006, NagC represses the transcription of two divergent operons, nagE and nagBAC, which encode proteins involved in the transport and metabolism of GlcNAc. Moreover, NagC directly binds to a 21-nt region that partially overlaps the -10 and -35 regions of the pig promoter and promotes the transcription of prodigiosin biosynthesis genes, thereby increasing prodigiosin production. Although NagC still acts as both repressor and activator in Serratia sp. ATCC 39006, its transcriptional regulatory activity is independent of GlcNAc. NagC was first found to regulate antibiotic biosynthesis in Gram-negative bacteria, and NagC-mediated regulation is not responsive to GlcNAc, which contributes to future studies on the regulation of secondary metabolism by NagC in other bacteria. IMPORTANCE: The ROK family transcription factor NagC is an important global regulator in the γ-proteobacteria. A large number of genes involved in the transport and metabolism of sugars, as well as those associated with biofilm formation and pathogenicity, are regulated by NagC. In all of these regulations, the transcriptional regulatory activity of NagC responds to the supply of GlcNAc in the environment. Here, we found for the first time that NagC can regulate antibiotic biosynthesis, whose transcriptional regulatory activity is independent of GlcNAc. This suggests that NagC may respond to more signals and regulate more physiological processes in Gram-negative bacteria.
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Acetilglucosamina , Proteínas Bacterianas , Regulación Bacteriana de la Expresión Génica , Prodigiosina , Serratia , Serratia/genética , Serratia/metabolismo , Prodigiosina/biosíntesis , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Acetilglucosamina/metabolismo , Operón , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Although functional studies on carbohydrate-binding module (CBM) have been carried out extensively, the role of tandem CBMs in the enzyme containing multiple catalytic domains (CDs) is unclear. Here, we identified a multidomain enzyme (Lc25986) with a novel modular structure from lignocellulolytic bacterial consortium. It consists of a mannanase domain, two CBM65 domains (LcCBM65-1/LcCBM65-2), and an esterase domain. To investigate CBM function and domain interactions, full-length Lc25986 and its variants were constructed and used for enzymatic activity, binding, and bioinformatic analyses. The results showed that LcCBM65-1 and LcCBM65-2 both bind mannan and xyloglucan but not cellulose or ß-1,3-1,4-glucan, which differs from the ligand specificity of reported CBM65s. Compared to LcCBM65-2, LcCBM65-1 showed a stronger ligand affinity and a preference for acetylation sites. Both CBM65s stimulated the enzymatic activities of their respective neighboring CDs against acetylated mannan, but did not contribute to the activities of the distal CDs. The time course of mannan hydrolysis indicated that the full-length Lc25986 was more effective in the complete degradation of mixed acetyl/non-acetyl substrates than the mixture of single-CD mutants. When acting on complex substrates, LcCBM65-1 not only improved the enzymatic activity of the mannanase domain, but also directed the esterase domain to the acetylated polysaccharides. LcCBM65-2 adopted a low affinity to reduce interference with the catalysis of the mannanase domain. These results demonstrate the importance of CBMs for the synergism between the two CDs of a multidomain enzyme and suggest that they contribute to the adequate degradation of complex substrates such as plant cell walls. IMPORTANCE: Lignocellulolytic enzymes, particularly those of bacterial origin, often harbor multiple carbohydrate-binding modules (CBMs). However, the function of CBM multivalency remains poorly understood. This is especially true for enzymes that contain more than one catalytic domain (CD), as the interactions between CDs, CBMs, and CDs and CBMs can be complex. Our research demonstrates that homogeneous CBMs can have distinct functions in a multimodular enzyme. The tandem CBMs coordinate the CDs in catalytic conflict through their differences in binding affinity, ligand preference, and arrangement within the full-length enzyme. Additionally, although the synergism between mannanase and esterase is widely acknowledged, our study highlights the benefits of integrating the two enzymes into a single entity for the degradation of complex substrates. In summary, these findings enhance our understanding of the intra-synergism of a multimodular enzyme and emphasize the significance of multiple CBMs in this context.
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Proteínas Bacterianas , Dominio Catalítico , Glucanos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Glucanos/metabolismo , Xilanos/metabolismo , Mananos/metabolismo , Lignina/metabolismo , Bacterias/enzimología , Bacterias/genética , Hidrólisis , Especificidad por SustratoRESUMEN
Stripe rust is a devastating disease of wheat worldwide. Chinese wheat cultivar Lanhangxuan 121 (LHX121), selected from an advanced line L92-47 population that had been subjected to space mutation breeding displayed a consistently higher level of resistance to stipe rust than its parent in multiple field environments. The aim of this research was to establish the number and types of resistance genes in parental lines L92-47 and LHX121 using separate segregating populations. The first population developed from a cross between LHX121 and susceptible cultivar Xinong 822 comprised 278 F2:3 lines. The second validation population comprised 301 F2:3 lines from a cross between L92-47 and susceptible cultivar Xinong 979. Lines of two population were evaluated for stripe rust response at three sites during the 2018-2020 cropping season. Affymetrix 660 K SNP arrays were used to genotype the lines and parents. Inclusive composite interval mapping detected QTL QYrLHX.nwafu-2BS, QYrLHX.nwafu-3BS, and QYrLHX.nwafu-5BS for resistance in all three environments. Based on previous studies and pedigree information, QYrLHX.nwafu-2BS and QYrLHX.nwafu-3BS were likely to be Yr27 and Yr30 that are present in the L92-47 parent. QYrLHX.nwafu-5BS (YrL121) detected only in LHX121 was mapped to a 7.60 cM interval and explained 10.67-22.57% of the phenotypic variation. Compared to stripe rust resistance genes previously mapped to chromosome 5B, YrL121 might be a new adult plant resistance QTL. Furthermore, there were a number of variations signals using 35 K SNP array and differentially expressed genes using RNA-seq between L92-47 and LHX121 in the YrL121 region, indicating that they probably impair the presence and/or function of YrL121. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01461-0.
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Rheumatoid arthritis (RA) involves chronic joint inflammation. Combining acupuncture and medication for RA treatment faces challenges like spatiotemporal variability, limited drug loading in acupuncture needles, and premature or untargeted drug release. Here, we designed a new type of tubular acupuncture needles, with an etched hollow honeycomb-like structure to enable the high loading of therapeutics, integrating the traditional acupuncture and drug repository into an all-in-one therapeutic platform. In these proof-of-concept experiments, we fabricated injectable hollow honeycomb electroacupuncture needles (HC-EA) loaded with melittin hydrogel (MLT-Gel), enabling the combination treatment of acupuncture stimulation and melittin therapy in a spatiotemporally synchronous manner. Since the RA microenvironment is mildly acidic, the acid-responsive chitosan (CS)/sodium beta-glycerophosphate (ß-GP)/ hyaluronic acid (HA) composited hydrogel (CS/GP/HA) was utilized to perform acupuncture stimulation and achieve the targeted release of injected therapeutics into the specific lesion site. Testing our therapeutic platform involved a mouse model of RA and bioinformatics analysis. MLT-Gel@HC-EA treatment restored Th17/Treg-mediated immunity balance, reduced inflammatory factor release (TNF-α, IL-6, IL-1ß), and alleviated inflammation at the lesion site. This novel combination of modified acupuncture needle and medication, specifically melittin hydrogel, holds promise as a therapeutic strategy for RA treatment.
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Terapia por Acupuntura , Artritis Reumatoide , Hidrogeles , Meliteno , Agujas , Animales , Meliteno/farmacología , Meliteno/química , Ratones , Artritis Reumatoide/terapia , Artritis Reumatoide/tratamiento farmacológico , Hidrogeles/química , Terapia por Acupuntura/métodos , Quitosano/química , Ácido Hialurónico/química , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.
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Conducta Animal , Depresión/patología , Sustancia Gris Periacueductal/patología , Receptor de Galanina Tipo 1/metabolismo , Factores de Transcripción/metabolismo , Animales , Elementos E-Box/genética , Neuronas GABAérgicas/metabolismo , Regulación de la Expresión Génica , Ácido Glutámico/metabolismo , Células PC12 , Regiones Promotoras Genéticas/genética , Unión Proteica , Ratas , Receptor de Galanina Tipo 1/genética , Estrés Psicológico/complicaciones , Factores de Transcripción/genética , Sitio de Iniciación de la TranscripciónRESUMEN
The incidence of colibacillosis in poultry is on the rise, significantly affecting the chicken industry. Ceftiofur sodium (CS) is frequently employed to treat this disease, resulting in lipopolysaccharide (LPS) buildup. Processing plays a vital role in traditional Chinese veterinary medicine. The potential intervention in liver injury by polysaccharides from the differently processed products of Angelica sinensis (PDPPAS) induced by combined CS and LPS remains unclear. This study aims to investigate the protective effect of PDPPAS on chicken liver injury caused by CS combined with LPS buildup and further identify the polysaccharides with the highest hepatoprotective activity in chickens. Furthermore, the study elucidates polysaccharides' intervention mechanism using tandem mass tag (TMT) proteomics and multiple reaction monitoring (MRM) methods. A total of 190 1-day-old layer chickens were randomly assigned into 12 groups, of which 14 chickens were in the control group and 16 in other groups, for a 10-day trial. The screening results showed that charred A. sinensis polysaccharide (CASP) had the most effective and the best hepatoprotective effect at 48 h. TMT proteomics and MRM validation results demonstrated that the intervention mechanism of the CASP high-dose (CASPH) intervention group was closely related to the protein expressions of FCER2, TBXAS1, CD34, AGXT, GCAT, COX7A2L, and CYP2AC1. Conclusively, the intervention mechanism of CASPH had multitarget, multicenter regulatory features.
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Angelica sinensis , Pollos , Hígado , Polisacáridos , Proteómica , Espectrometría de Masas en Tándem , Animales , Angelica sinensis/química , Proteómica/métodos , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/análisis , Espectrometría de Masas en Tándem/métodos , Hígado/efectos de los fármacos , Hígado/metabolismo , Proteoma/análisis , Proteoma/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & controlRESUMEN
The rapid growth of electronic devices, electric vehicles, and mobile energy storage has produced large quantities of spent batteries, leading to significant environmental issues and a shortage of lithium resources. Recycling spent batteries has become urgent to protect the environment. The key to treating spent lithium-ion batteries is to implement green and efficient regeneration. This study proposes a recycling method for the direct regeneration of spent lithium iron phosphate (LFP) batteries using hydrothermal reduction. Ascorbic acid (AA) was used as a low-cost and environmentally friendly reductant to reduce Fe3+ in spent LiFePO4. We also investigated the role of AA in the hydrothermal process and its effects on the electrochemical properties of the regenerated LiFePO4 cathode material (AA-SR-LFP). The results showed that the hydrothermal reduction direct regeneration method successfully produced AA-SR-LFP with good crystallinity and electrochemical properties. AA-SR-LFP exhibited excellent electrochemical properties, with an initial discharge specific capacity of 144.4 mAh g-1 at 1 C and a capacity retention rate of 98.6% after 100 cycles. In summary, the hydrothermal reduction direct regeneration method effectively repairs the defects in the chemical composition and crystal structure of spent LiFePO4. It can be regarded as a green and effective regeneration approach for spent LiFePO4 cathode materials.
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BACKGROUND: Skeletal muscle is the largest tissue in the body, and it affects motion, metabolism and homeostasis. Skeletal muscle development comprises myoblast proliferation, fusion and differentiation to form myotubes, which subsequently form mature muscle fibres. This process is strictly regulated by a series of molecular networks. Increasing evidence has shown that noncoding RNAs, especially microRNAs (miRNAs), play vital roles in regulating skeletal muscle growth. Here, we showed that miR-668-3p is highly expressed in skeletal muscle. METHODS: Proliferating and differentiated C2C12 cells were transfected with miR-668-3p mimics and/or inhibitor, and the mRNA and protein levels of its target gene were evaluated by RTâqPCR and Western blotting analysis. The targeting of Appl1 by miR-668-3p was confirmed by dual luciferase assay. The interdependence of miR-668-3p and Appl1 was verified by cotransfection of C2C12 cells. RESULTS: Our data reveal that miR-668-3p can inhibit myoblast proliferation and myogenic differentiation. Phosphotyrosine interacting with PH domain and leucine zipper 1 (Appl1) is a target gene of miR-668-3p, and it can promote myoblast proliferation and differentiation by activating the p38 MAPK pathway. Furthermore, the inhibitory effect of miR-668-3p on myoblast cell proliferation and myogenic differentiation could be rescued by Appl1. CONCLUSION: Our results indicate a new mechanism by which the miR-668-3p/Appl1/p38 MAPK pathway regulates skeletal muscle development.
Asunto(s)
MicroARNs , Línea Celular , Diferenciación Celular/genética , MicroARNs/genética , MicroARNs/metabolismo , Mioblastos , Proliferación Celular/genética , Desarrollo de Músculos/genéticaRESUMEN
BACKGROUND: Several studies have indicated that magnetic resonance imaging radiomics can predict survival in patients with breast cancer, but the potential biological underpinning remains indistinct. Herein, we aim to develop an interpretable deep-learning-based network for classifying recurrence risk and revealing the potential biological mechanisms. METHODS: In this multicenter study, 1113 nonmetastatic invasive breast cancer patients were included, and were divided into the training cohort (n = 698), the validation cohort (n = 171), and the testing cohort (n = 244). The Radiomic DeepSurv Net (RDeepNet) model was constructed using the Cox proportional hazards deep neural network DeepSurv for predicting individual recurrence risk. RNA-sequencing was performed to explore the association between radiomics and tumor microenvironment. Correlation and variance analyses were conducted to examine changes of radiomics among patients with different therapeutic responses and after neoadjuvant chemotherapy. The association and quantitative relation of radiomics and epigenetic molecular characteristics were further analyzed to reveal the mechanisms of radiomics. RESULTS: The RDeepNet model showed a significant association with recurrence-free survival (RFS) (HR 0.03, 95% CI 0.02-0.06, P < 0.001) and achieved AUCs of 0.98, 0.94, and 0.92 for 1-, 2-, and 3-year RFS, respectively. In the validation and testing cohorts, the RDeepNet model could also clarify patients into high- and low-risk groups, and demonstrated AUCs of 0.91 and 0.94 for 3-year RFS, respectively. Radiomic features displayed differential expression between the two risk groups. Furthermore, the generalizability of RDeepNet model was confirmed across different molecular subtypes and patient populations with different therapy regimens (All P < 0.001). The study also identified variations in radiomic features among patients with diverse therapeutic responses and after neoadjuvant chemotherapy. Importantly, a significant correlation between radiomics and long non-coding RNAs (lncRNAs) was discovered. A key lncRNA was found to be noninvasively quantified by a deep learning-based radiomics prediction model with AUCs of 0.79 in the training cohort and 0.77 in the testing cohort. CONCLUSIONS: This study demonstrates that machine learning radiomics of MRI can effectively predict RFS after surgery in patients with breast cancer, and highlights the feasibility of non-invasive quantification of lncRNAs using radiomics, which indicates the potential of radiomics in guiding treatment decisions.