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Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous ß-phenylethylamine (ß-PEA)1 as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and ß-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.
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Metanfetamina , Fenetilaminas , Receptores Acoplados a Proteínas G , Humanos , Ligandos , Metanfetamina/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Fenetilaminas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Polifarmacología , Enlace de HidrógenoRESUMEN
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
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Linfocitos B/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Inmunoterapia , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Estructuras Linfoides Terciarias/inmunología , Linfocitos B/citología , Linfocitos B/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Células Clonales/citología , Células Clonales/inmunología , Células Clonales/metabolismo , Células Dendríticas Foliculares/citología , Células Dendríticas Foliculares/inmunología , Regulación Neoplásica de la Expresión Génica , Humanos , Memoria Inmunológica/inmunología , Espectrometría de Masas , Melanoma/patología , Melanoma/cirugía , Metástasis de la Neoplasia/genética , Fenotipo , Pronóstico , RNA-Seq , Receptores Inmunológicos/inmunología , Análisis de la Célula Individual , Linfocitos T/citología , Linfocitos T/inmunología , TranscriptomaRESUMEN
Azoospermia and asthenospermia are common manifestations of male infertility, but it needs further studies to understand the intrinsic regulation mechanism. As a popular model organism, zebrafish is often used to assess reproductive complications. In this study, by analyzing miRNA transcriptome of the mature triploid zebrafish testis afflicted with spermatogenic dysfunctions, leading to the identification of 36 miRNAs that are differentially expressed in comparison with diploid, which are predicted to target 2737 genes. Subsequent functional annotation of these genes pinpointed two miRNAs might association with spermatogenesis. Inhibitory experiments showed that NC_007115.7.7_998413 inhibited conducts a substantial decline in sperm density, and conducted lower embryo fertilization rate than control. And putative target genes qRT-PCR evaluation showed that spata2 was significant down-regulate upon inhibited NC_007115.7.7_998413. In summary, this research positions newly identified miRNA NC_007115.7.998413 as a regulatory factor in male zebrafish reproductive development, enhancing our comprehension of the molecular regulated pathways involved in spermatogenesis.
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Infertilidad Masculina , MicroARNs , Humanos , Animales , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Pez Cebra/genética , Semen/metabolismo , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Testículo/metabolismo , Espermatogénesis/genéticaRESUMEN
GCN2-eIF2α signaling pathway plays crucial roles in cell growth,development, and protein synthesis. However, in polyploid fish, the function of this pathway is rarely understood. In this study, genes associated with the GCN2-eIF2α pathway (pkr, pek, gcn2, eif2α) are founded lower expression levels in the triploid crucian carp (3nCC) muscle compared to that of the red crucian carp (RCC). In muscle effect stage embryos of the 3nCC, the mRNA levels of this pathway genes are generally lower than those of RCC, excluding hri and fgf21. Inhibiting gcn2 in 3nCC embryos downregulates downstream gene expression (eif2α, atf4, fgf21), accelerating embryonic development. In contrast, overexpressing of eif2α can alter the expression levels of downstream genes (atf4 and fgf21), and decelerates the embryonic development. These results demonstrate the GCN2-eIF2α pathway's regulatory impact on 3nCC growth, advancing understanding of fish rapid growth genetics and offering useful molecular markers for breeding of excellent strains.
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Carpas , Factor 2 Eucariótico de Iniciación , Proteínas de Peces , Transducción de Señal , Animales , Carpas/genética , Carpas/metabolismo , Carpas/crecimiento & desarrollo , Factor 2 Eucariótico de Iniciación/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Triploidía , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Regulación del Desarrollo de la Expresión Génica , Desarrollo Embrionario/genéticaRESUMEN
BACKGROUND: Medical consortiums have been extensively established to facilitate the integration of health resources and bridge the technical gap among member institutions. However, some commonly appropriate technologies remain stagnant in subordinate hospitals, although they have been routinely applied in leading hospitals. Besides, the mechanism underlying differences in clinicians' adoption behavior at different levels of institutions was unknown. Therefore, this study aimed to investigate the differences in influencing mechanisms of clinicians' hepatic contrast-enhanced ultrasound technology (CEUS) utilization behavior between leading and subordinate hospitals within medical consortiums, thus providing clues for expanding effective and appropriate technologies within integrated care systems. METHODS: A self-designed scale was developed based on the theory of planned behavior (TPB). A multistage sampling method was applied to investigate clinicians who were aware of CEUS and worked in liver disease-related departments within the sampled medical institutions. The final sample size was 289. AMOS 24.0 software was used to construct multi-group structural equation modeling (SEM) to validate the hypotheses and determine the mechanism of hepatic CEUS utilization. RESULTS: It revealed that behavioral intention significantly influenced adoption behavior, regardless of whether it was in leading hospitals or subordinate hospitals (ß = 0.283, p < 0.001). Furthermore, behavioral attitude (ß = 0.361, p < 0.001) and perceived behavioral control (ß = 0.582, p < 0.001) exerted significant effects on adoption behavior through behavioral intention. However, in leading hospitals, subjective norm had a significant positive effect on behavioral intention (ß = 0.183, p < 0.01), while it had a significant negative impact on behavioral intention in the subordinate hospitals (ß = -0.348, p < 0.01). CONCLUSION: To effectively translate the adoption intention into actual behavior, it is recommended to elucidate the demand and facilitators involved in the process of health technology adoption across leading and subordinate hospitals. Additionally, bolstering technical support and knowledge dissemination within subordinate hospitals while harnessing the influential role of key individuals can further enhance this transformative process.
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Detección Precoz del Cáncer , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/psicología , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Femenino , Detección Precoz del Cáncer/psicología , Detección Precoz del Cáncer/métodos , Actitud del Personal de Salud , Ultrasonografía/métodos , Hospitales , Adulto , Encuestas y Cuestionarios , Medios de Contraste , Pautas de la Práctica en MedicinaRESUMEN
BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Humanos , Sunitinib/farmacología , Sunitinib/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Vía de Señalización Wnt , beta Catenina/genética , beta Catenina/metabolismo , Pez Cebra/metabolismo , Línea Celular Tumoral , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Transición Epitelial-Mesenquimal/genética , Movimiento Celular , Proliferación CelularRESUMEN
Tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) has come into use as an alternative to hexabromocyclododecane (HBCD), but it is unclear whether TBBPA-DBMPE has less hazard than HBCD. Here, we compared the bioaccumulation and male reproductive toxicity between TBBPA-DBMPE and HBCD in mice following long-term oral exposure after birth. We found that the concentrations of TBBPA-DBMPE in livers significantly increased with time, exhibiting a bioaccumulation potency not substantially different from HBCD. Lactational exposure to 1000 µg/kg/d TBBPA-DBMPE as well as 50 µg/kg/d HBCD inhibited testis development in suckling pups, and extended exposure up to adulthood resulted in significant molecular and cellular alterations in testes, with slighter effects of 50 µg/kg/d TBBPA-DBMPE. When exposure was extended to 8 month age, severe reproductive impairments including reduced sperm count, increased abnormal sperm, and subfertility occurred in all treated animals, although 50 µg/kg/d TBBPA-DBMPE exerted lower effects than 50 µg/kg/d HBCD. Altogether, all data led us to conclude that TBBPA-DBMPE exerted weaker male reproductive toxicity than HBCD at the same doses but exhibited bioaccumulation potential roughly equivalent to HBCD. Our study fills the data gap regarding the bioaccumulation and toxicity of TBBPA-DBMPE and raises concerns about its use as an alternative to HBCD.
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Retardadores de Llama , Hidrocarburos Bromados , Bifenilos Polibrominados , Masculino , Animales , Ratones , Retardadores de Llama/toxicidad , Éter , Bioacumulación , Semen , Hidrocarburos Bromados/toxicidad , Bifenilos Polibrominados/toxicidad , Éteres , Éteres de EtilaRESUMEN
The Yangtze River Delta (YRD), one of the most economically developed and industrialized regions in China, is confronted with challenges arising from rapid urbanization, particularly environmental pollution. The collection of surface water and sediment samples from forty-nine sites in the YRD was conducted to analyze 2378-substituted polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) congeners. The detected concentrations of PCDD/Fs were 0-5.3 pg TEQ/L in water and 0.12-1493 pg TEQ/g dw in sediment. The PCDD/Fs contamination in the sediment was widespread in the YRD. There were variations in the congener characteristics of PCDD/Fs in surface water and sediment. The proportion of OCDD was significantly lower in surface water samples compared to sediment, while the less chlorine-substituted homologs were found in larger proportions. To understand the partitioning and behavior of dioxins within the water-sediment system, we calculated the organic carbon normalized partition coefficients and fugacity fraction (ff) of PCDD/F congeners. The results revealed that the PCDD/Fs had not attained a state of distributional equilibrium, and the non-specific hydrophobic effect seemed minimally influential on their partitioning between sediment and water. The average ff values, which varied between 0.06 and 0.63, indicated differing migration directions for the PCDD/F congeners. Source identification analysis provided evidence that the dioxins in the river water were primarily attributed to industrial thermal processes. Iron and steel smelting, along with pesticide production and use, were likely responsible for the sediment contamination. This comprehensive analysis underscores the complex nature of PCDD/Fs pollution in the YRD and highlights the necessity for targeted environmental management strategies.
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Dibenzofuranos Policlorados , Monitoreo del Ambiente , Sedimentos Geológicos , Dibenzodioxinas Policloradas , Ríos , Contaminantes Químicos del Agua , China , Sedimentos Geológicos/química , Sedimentos Geológicos/análisis , Dibenzodioxinas Policloradas/análisis , Contaminantes Químicos del Agua/análisis , Dibenzofuranos Policlorados/análisis , Ríos/química , Benzofuranos/análisisRESUMEN
BACKGROUND: At present, several cross-sectional studies have found that exposure to metal/metalloid elements is closely associated with male reproduction. However, the long-term effects of metal exposure on male reproduction have not been explored. METHODS: In 2013, 796 volunteers were recruited, followed by first and second follow-ups in 2014 and 2015. Urine, semen, and blood samples were collected at each stage to examine urinary metal/metalloid levels, sperm parameters, and sex hormones. Initially, the latent class trajectory model (LCTM) was utilized to analyze the trajectories of urinary metals. Subsequently, the effects of urinary metal trajectories on semen parameters and sex hormones were examined using the linear mixed model. Finally, the impact of urinary metal trajectories on the classification of semen quality (normal or abnormal) was evaluated using the generalized linear mixed model. RESULTS: Among the 18 metals/metalloids studied, trajectories were formed by 6 of them (Li, Al, Fe, Zn, As, Rb). Further analysis using the linear mixed model and the generalized linear mixed model revealed that Li was negatively correlated with semen volume, and sperm motility (P<0.05). The maximum-decreasing trajectory group had a detrimental effect on semen quality (OR=1.75, 95%CI: 1.22, 2.53) compared to the minimum-stable trajectory group. Al showed negative associations with sperm concentration, total sperm count, and normal morphology (P<0.05). Rb was positively associated with progressive motility (P<0.05). The high-stable trajectory group exhibited a protective effect on semen quality (OR=0.66, 95%CI: 0.49, 0.90) compared to the low-stable trajectory group. Additionally, Fe was observed to have a negative relationship with follicle-stimulating hormone (FSH) (P<0.05), and Rb exhibited a negative correlation with progesterone (P) (P<0.05). CONCLUSION: Our three-year cohort study provides new evidence that Li and Al have a negative impact on semen quality, whereas Rb is associated with beneficial effects. Additionally, Rb and Fe are endocrine disruptors of sex hormones.
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Segmental bone defects, arising from factors such as trauma, tumor resection, and congenital malformations, present significant clinical challenges that often necessitate complex reconstruction strategies. Hydrogels loaded with multiple osteogenesis-promoting components have emerged as promising tools for bone defect repair. While the osteogenic potential of the Piezo1 agonist Yoda1 has been demonstrated previously, its hydrophobic nature poses challenges for effective loading onto hydrogel matrices.In this study, we address this challenge by employing Yoda1-pretreated bone marrow-derived mesenchymal stem cell (BMSCs) exosomes (Exo-Yoda1) alongside exosomes derived from BMSCs (Exo-MSC). Comparatively, Exo-Yoda1-treated BMSCs exhibited enhanced osteogenic capabilities compared to both control groups and Exo-MSC-treated counterparts. Notably, Exo-Yoda1-treated cells demonstrated similar functionality to Yoda1 itself. Transcriptome analysis revealed activation of osteogenesis-associated signaling pathways, indicating the potential transduction of Yoda1-mediated signals such as ErK, a finding validated in this study. Furthermore, we successfully integrated Exo-Yoda1 into gelatin methacryloyl (GelMA)/methacrylated sodium alginate (SAMA)/ß-tricalcium phosphate (ß-TCP) hydrogels. These Exo-Yoda1-loaded hydrogels demonstrated augmented osteogenesis in subcutaneous ectopic osteogenesis nude mice models and in rat skull bone defect model. In conclusion, our study introduces Exo-Yoda1-loaded GELMA/SAMA/ß-TCP hydrogels as a promising approach to promoting osteogenesis. This innovative strategy holds significant promise for future widespread clinical applications in the realm of bone defect reconstruction.
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Exosomas , Hidrogeles , Células Madre Mesenquimatosas , Osteogénesis , Osteogénesis/efectos de los fármacos , Animales , Exosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Hidrogeles/química , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Ratas , Masculino , Alginatos/química , Gelatina/química , Diferenciación Celular/efectos de los fármacos , Regeneración Ósea/efectos de los fármacos , Células CultivadasRESUMEN
INTRODUCTION: Gallic acid (GA) has a good therapeutic effect in bacteriological inhibition and plays a variety of functions in maintaining the stability of the immune system. The aim of the present study was to investigate the effect of GA on the bactericidal activity of macrophages against Vibrio vulnificus (Vv). METHODS: A cell counting kit-8 (CCK-8) assay was carried out to test the cytotoxicity of GA on J774A.1 cells. Concentration of proinflammatory cytokines in J774A.1 cells were evaluated by ELISA. The internalization and degradation of Vv in the phagosomes were observed by transmission electron microscopy (TEM). The phagosome acidification and phagolysosome formation were detected to evaluate the bacteria-clearing function of J774A.1 cells. The bactericidal activity of GA in vivo was also investigated by collecting the survival time of Vv infected mice and observing the inflammatory infiltration of organs. RESULTS: Our results demonstrated that GA at 50 µM significantly inhibited the proinflammatory cytokines levels, promoted phagosome acidification and phagolysosome formation in J774A.1 cells with Vv infection. This may be related to the activation of NLRP3/mTOR signaling pathway. Additionally, GA treatment improves the survival and bactericidal activity of mice infected with Vv. CONCLUSIONS: In summary, GA exerts bactericidal activity against Vv infection by regulating the formation and acidification of phagocytic lysosomes in macrophages.
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Ácido Gálico , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Fagosomas , Transducción de Señal , Serina-Treonina Quinasas TOR , Vibrio vulnificus , Ácido Gálico/farmacología , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Fagosomas/efectos de los fármacos , Fagosomas/metabolismo , Vibrio vulnificus/efectos de los fármacos , Línea Celular , Citocinas/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , FemeninoRESUMEN
Current literatures suggest a growing body of evidence highlighting the pivotal role of Immunogenic Cell Death (ICD) in multiple tumor types. Nevertheless, the potential and mechanisms of ICD in diffuse large B-cell lymphoma (DLBCL) remain inadequately studied. To address this gap, our current study aims to examine the impact of ICD on DLBCL and identify a corresponding gene signature in DLBC. Using the expression profiles of ICD-associated genes, the gene expression omnibus (GEO) samples were segregated into ICD-high and ICD-low subtypes utilizing non-negative matrix factorization clustering. Next, univariate and LASSO Cox regression analyses were employed to establish the ICD-related gene signature. Subsequently, the CIBERSORT tool, ssGSEA, and ESTIMATE algorithm were utilized to examine the association between the signature and tumor immune microenvironment of DLBC. Finally, the oncoPredict algorithm was implemented to evaluate the drug sensitivity prediction of DLBCL patients. These findings suggest that the immune microenvironment of the ICD-high group with a poor prognosis was significantly suppressed. An 8-gene ICD-related signature was identified and validated to prognosticate and evaluate the tumor immune microenvironment in DLBCL. Similarly, the high-risk group exhibited a worse prognosis compared to the low-risk group, and the immune function was considerably suppressed. Moreover, the results of oncoPredict algorithm indicated that patients in the high-risk group exhibited higher sensitivity to Cisplatin, Cytarabine, Epirubicin, Oxaliplatin, and Vincristine with low IC50. In conclusion, the present study provides novel insights into the role of ICD in DLBCL by identifying a new biomarker for the disease and may have implications for the development of immune-targeted therapies for the tumor.
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Mitochondrial function can be regulated by ion channels. Mitochondrial RNA splicing 2 (Mrs2) is a magnesium ion (Mg2+) channel located in the inner mitochondrial membrane, thereby mediating the Mg2+ influx into the mitochondrial matrix. However, its potential role in regulating the Mg homeostasis and mitochondrial function in aquatic species is still unclear. This study molecularly characterizes the gene encoding Mrs2 in fish M. amblycephala with its functions in maintaining the Mg homeostasis and mitochondrial function verified. The mrs2 gene is 2133 bp long incorporating a 1269 bp open reading frame, which encodes 422 amino acids. The Mrs2 protein includes two transmembrane domains and a conserved tripeptide Gly-Met-Asn, and has a high homology (65.92-97.64%) with those of most vertebrates. The transcript of mrs2 was relatively high in the white muscle, liver and kidney. The inhibition of mrs2 reduces the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the activities of mitochondrial complex I and V in hepatocytes. However, the over-expression of mrs2 increases the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the complex V activity, but decreases the activities of mitochondrial complex III and IV and citrate synthase in hepatocytes. Collectively, Mrs2 is highly conserved among different species, and is prerequisite for maintaining Mg homeostasis and mitochondrial function in fish.
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The synchronous meshing of the gear pair and the screw pair is a typical feature of the planetary roller screw mechanism. In order to fully derive and analyze the nonlinear dynamic characteristics of the system, this paper creatively incorporates the time-varying meshing stiffness of gear pair and the comprehensive transmission error into the research content. Combined with the thread contact force and friction force between the roller and the screw and between the roller and the nut, the nonlinear dynamic model of the planetary roller screw mechanism considering the meshing excitation of the gear pair is established. According to the time domain diagram, frequency domain diagram, phase plane diagram, Poincaré section diagram, three-dimensional spectrum diagram, and spatial phase diagram, the nonlinear behavior of the system is described in detail, and the bifurcation evolution process of the system under the excitation frequency parameters of the external load is revealed. In addition, based on the theory of multi-scale method and considering the variables such as meshing stiffness, meshing damping, and load fluctuation, the stability equation of the primary resonance of the system is derived. The analysis of the stability of the system under different working conditions shows that the parameters are selected within a reasonable range, which effectively reduces the primary common amplitude value and enhances the overall stability of the system. The research content improves the previous system dynamics modeling method and provides a theoretical basis for the nonlinear dynamics modeling method and parameter optimization design of the planetary roller screw mechanism.
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BACKGROUND: This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. METHODS: A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. RESULTS: The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study's duration. CONCLUSIONS: This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.
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Diterpenos , Medicamentos Herbarios Chinos , Glomerulonefritis Membranosa , Síndrome Nefrótico , Humanos , Persona de Mediana Edad , Diterpenos/efectos adversos , Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/efectos adversos , Síndrome Nefrótico/tratamiento farmacológico , Estudios ProspectivosRESUMEN
Cannabinoid metabolites have been reported to be more potent than their parent compounds. Among them, ajulemic acid (AJA) is a side-chain analog of Δ9-THC-11-oic acid, which would be a good template structure for the discovery of more potent analogues. Herein, we optimized the key allylic oxidation step to introduce the C-11 hydroxy group with a high yield. A series of compounds was prepared with this condition applied including HU-210, 11-nor-Δ8-tetrahydrocannabinol (THC)-carboxylic acid and Δ9-THC-carboxylic acid.
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Cannabinoides , Dronabinol , Cannabinoides/metabolismo , Ácidos CarboxílicosRESUMEN
This study developed a recombinant Bacillus subtilis to carry the LGSPDVIVIR peptide (cmP4) isolated from the hydrolyzed products of cottonseed meal with excellent antioxidant and immune-enhancing properties in vitro. It was carried as a tandem of five cmP4 peptides (cmP4') to be stably expressed on a large scale. Then, its effectiveness was evaluated in Chinese mitten crab (Eriocheir sinensis) based on growth performance, redox defense, and innate immunity. A total of 280 crabs (mean body weight: 41.40 ± 0.14) were randomly assigned to seven diets including a control one (without B. subtilis) and six experimental ones with different doses (107,108, and 109 CFU/kg) of unmodified and recombinant B. subtilis, respectively, for 12 weeks. Each diet was tested in four tanks of crabs (10/tank). In terms of bacterial dosages, the final weight (FW), weight gain (WG), hemolymph and hepatopancreatic activities of superoxide dismutase (SOD), catalase (CAT), lysosome (LZM), acid phosphatase (ACP) and alkaline phosphatase (AKP), and hepatopancreatic transcriptions of cat, mitochondrial manganese superoxide dismutase (mtmnsod), thioredoxin-1 (trx1), and prophenoloxidase (propo) all increased significantly with increasing B. subtilis dosages, while hemolymph and hepatopancreatic malondialdehyde (MDA) content and the transcriptions of toll like receptors (tlrs), NF-κB-like transcription factor (relish), and lipopolysaccharide-induced TNF-α factor (litaf) all decreased remarkably. In terms of bacterial species, the recombinant B. subtilis group obtained significantly high values of FW, WG, hemolymph, and hepatopancreatic activities of SOD, CAT, LZM, ACP, and AKP, and the transcriptions of mtmnsod, peroxiredoxin 6 (prx6), and propo compared with the unmodified B. subtilis, while opposite results were noted in hemolymph and hepatopancreatic MDA content and the transcriptions of tlrs, relish, and litaf. These results indicated that dietary supplementation with 109 CFU/kg of recombinant B. subtilis can improve the growth performance, redox defense, and nonspecific immunity of E. sinensis.
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Adenosine monophosphate-activated protein kinase (AMPK) is a sensor of cellular energy changes and controls food intake. This study investigates the effect of a high-calorie diet (high fat diet [HFD], high carbohydrate diet [HCD] and high energy diet [HED]) on appetite and central AMPK in blunt snout bream. In the present study, fish (average initial weight 45.84 ± 0.07 g) were fed the control, HFD, HCD and HED in four replicates for 12 weeks. At the end of the feeding trial, the result showed that body mass index, specific growth rate, feed efficiency ratio and feed intake were not affected (p > 0.05) by dietary treatment. However, fish fed the HFD obtained a significantly higher (p < 0.05) lipid productive value, lipid gain and lipid intake than those fed the control diet, but no significant difference was attributed to others. Also, a significantly higher (p < 0.05) energy intake content was found in fish-fed HFD, HCD and HED than those given the control diet. Long-term HFD and HCD feeding significantly increased (p < 0.05) plasma glucose, glycated serum protein, advanced glycation end product, insulin and leptin content levels than the control group. Moreover, a significantly lower (p < 0.05) complex 1, 2 and 3 content was found in fish-fed HFD and HCD than in the control, but no differences (p > 0.05) were attributed to those in HED. Fish-fed HED significantly upregulated (p < 0.05) hypothalamic ampα 1 and ampα 2 expression, whereas the opposite trend was observed in the hypothalamic mammalian target of rapamycin than those in HFD and HCD compared to the control. However, hypothalamic neuropeptide y, peroxisome proliferator-activated receptor α (pparα), acetyl-coa oxidase and carnitine palmitoyltransferase 1 were significantly upregulated (p < 0.05) in the HCD group, while the opposite was seen in cholecystokinin expression compared to those in the control group. Our findings indicated that the central AMPK signal pathway and appetite were modulated according to the diet's energy level to regulate nutritional status and maintain energy homoeostasis in fish.
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Proteínas Quinasas Activadas por AMP , Cyprinidae , Animales , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Regulación del Apetito , Carbohidratos , Cyprinidae/metabolismo , Dieta/veterinaria , Dieta Alta en Grasa , Hipotálamo/metabolismo , Lípidos , Mamíferos/metabolismoRESUMEN
Hypoxia is the most significant factor that threatens the health and even survival of freshwater and marine fish. Priority should be given to the investigation of hypoxia adaptation mechanisms and their subsequent modulation. Acute and chronic studies were designed for the current study. Acute hypoxia comprised of normoxia dissolved oxygen (DO) 7.0 ± 0.5 mg/mL (N0), low-oxygen 5.0 ± 0.5 mg/mL(L0), and hypoxia 1.0 ± 0.1 mg/mL (H0) and 300 mg/L Vc for hypoxia regulation (N300, L300, H300). Chronic hypoxia comprised of normoxia (DO 7.0 ± 0.5 mg/mL) with 50 mg/kg Vc in the diet (N50) and low oxygen (5.0 ± 0.5 mg/mL) with 50, 250, 500 mg/kg Vc in the diet (L50, L250, L500) to assess the effect of Vc in hypoxia. The growth, behavior, hematological parameters, metabolism, antioxidants, and related inflammatory factors of channel catfish were investigated, and it was found that channel catfish have a variety of adaptive mechanisms in response to acute and chronic hypoxia. Under acute 5 mg/mL DO, the body color lightened (P < 0.05) and reverted to normal with 300 mg/mL Vc. PLT was significantly elevated after 300 mg/L Vc (P < 0.05), indicating that Vc can effectively restore hemostasis following oxygen-induced tissue damage. Under acute hypoxia, the significantly increased of cortisol, blood glucose, the gene of pyruvate kinase (pk), and phosphofructokinase (pfk), together with the decreased expression of fructose1,6-bisphosphatase (fbp) and the reduction in myoglycogen, suggested that Vc might enhance the glycolytic ability of the channel catfish. And the enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and the gene expression of sod rose significantly, showing that Vc might improve the antioxidant capacity of the channel catfish. The significant up-regulation of tumor necrosis factor-alpha (tnf-α), interleukin-1ß (il-1ß), and cd68 under acute hypoxia implies that hypoxia may generate inflammation in channel catfish, whereas the addition of Vc and down-regulation of these genes suggests that Vc suppresses inflammation under acute hypoxia. We found that the final weight, WGR, FCR, and FI of channel catfish were significantly reduced under chronic hypoxia, and that feeding 250 mg/kg of Vc in the diet was effective in alleviating the growth retardation caused by hypoxia. The significant increase in cortisol, blood glucose, myoglycogen, and the expression of tnf-α, il-1ß, and cd68 (P < 0.05) and the significant decrease in lactate (P < 0.05) under chronic hypoxia indicated that the channel catfish had gradually adapted to the survival threat posed by hypoxia and no longer relied on carbohydrates as their primary source of energy. While the addition of Vc did not appear to increase the energy supply of the fish under hypoxia in terms of glucose metabolism, but the significantly decreased expression of tnf-α, il-1ß, and cd68 (P < 0.05) also were found, indicating that chronic hypoxia, similar acute hypoxia, may increase inflammation in the channel catfish. This study indicates that under acute stress, channel catfish withstand stress by raising energy supply through glycolysis, and acute hypoxic stress significantly promotes inflammation in channel catfish, but Vc assists the channel catfish resist stress by raising glycolysis, antioxidant capacity, and decreasing the production of inflammatory markers. Under chronic hypoxia, the channel catfish no longer utilize carbohydrates as their primary energy source, and Vc may still effectively reduce inflammation in the channel catfish under hypoxia.
Asunto(s)
Antioxidantes , Ictaluridae , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Ictaluridae/fisiología , Hidrocortisona/metabolismo , Glucemia , Factor de Necrosis Tumoral alfa/metabolismo , Vitaminas , Hipoxia , Inflamación , Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
This study aimed to investigate the effects of dietary metformin supplementation on the redox balance, inflammation, mitochondrial biogenesis, and function in blunt snout bream fed a high-carbohydrate (HC) diet. Fish (45.12 ± 0.36 g) were randomly offered four diets, including a control diet (33% carbohydrate), an HC diet (45% carbohydrate), and the HC diet supplemented with 0.06% (HCM1) and 0.12% (HCM2) metformin respectively for 12 weeks. Compared with the control, feeding the HC diet significantly increased the hepatosomatic index (HSI), the mesenteric fat index, liver and muscle glycogen contents, liver and adipose tissue lipid contents, plasma glucose and glycation end products (AGES) levels and aspartate transaminase activity, plasma and liver malondialdehyde (MDA) contents, hepatic adenosine triphosphate (ATP) and adenosine monophosphate (AMP) contents, mitochondrial cytochrome c content, mitochondrial complex IV activity and ATP 6 transcription, but decreased plasma catalase (CAT) activity, muscle superoxide dismutase (SOD) activity, hepatic antioxidant enzymes activities, and the transcriptions of transforming growth factor ß (tgfß) and interleukin 10 (il10). Compared with the HC group, metformin treatment (especially the HCM2 group) significantly elevated tissue glycogen contents, muscle SOD activity, plasma and liver antioxidant enzymes activities, the transcriptions of tgfß and il10, the sodium/potassium ATPase activity, the contents of mitochondrial protein and AMP, the level of p-AMP activated protein kinase (AMPK), and the p-AMPK/t-AMPK ratio, but lowered the HSI, tissue lipid contents, plasma levels of glucose, AGES and glycated serum protein, plasma, and liver MDA contents, the transcriptions of il1ß, NADH dehydrogenase subunit 1 and ATP 6, the contents of ATP and cytochrome c, the ATP/AMP ratio, and the activities of complexes I and IV. In conclusion, metformin could attenuate the HC diet-induced redox imbalance, inflammation, and mitochondrial dysfunction in blunt snout bream.