RESUMEN
Electrochemical conversion of N2 into ammonia presents a sustainable pathway to produce hydrogen storage carrier but yet requires further advancement in electrocatalyst design and electrolyzer integration. This technology suffers from low selectivity and yield owing to the extremely strong N≡N bond and the exceptionally low solubility of N2 in aqueous systems. A high NH3 synthesis performance is restricted by the high activation energy of N≡N bond and the supply insufficiency of N2 to active sites. This paper describes the introduction of electron-rich Bi0 sites into Ag catalysts with a high-pressure electrolyzer that enables a dramatically enhanced Faradaic efficiency of 44.0% and yield of 28.43 µg cm-2 h-1 at 4.0 MPa. Combined with density functional theory results, in situ attenuated total reflectance surface-enhanced infrared absorption spectroscopy demonstrates that N2 reduction reaction follows an associative mechanism, in which a high coverage of N-N bond and -NH2 intermediates suggest electron-rich Bi0 boosts sound activation of N2 molecules and low hydrogenation barrier. The proposed strategy of engineering electrochemical catalysts and devices provides powerful guidelines for achieving industrial-level green ammonia production.
RESUMEN
Economic development and increased stress have considerably increased the prevalence of psychiatric disorders in recent years, which rank as some of the most prevalent diseases globally. Several factors, including chronic social stress, genetic inheritance, and autogenous diseases, lead to the development and progression of psychiatric disorders. Clinical treatments for psychiatric disorders include psychotherapy, chemotherapy, and electric shock therapy. Although various achievements have been made researching psychiatric disorders, the pathogenesis of these diseases has not been fully understood yet, and serious adverse effects and resistance to antipsychotics are major obstacles to treating patients with psychiatric disorders. Recent studies have shown that the mammalian target of rapamycin (mTOR) is a central signaling hub that functions in nerve growth, synapse formation, and plasticity. The PI3K-AKT/mTOR pathway is a critical target for mediating the rapid antidepressant effects of these pharmacological agents in clinical and preclinical research. Abnormal PI3K-AKT/mTOR signaling is closely associated with the pathogenesis of several neurodevelopmental disorders. In this review, we focused on the role of mTOR signaling and the related aberrant neurogenesis in psychiatric disorders. Elucidating the neurobiology of the PI3K-AKT/mTOR signaling pathway in psychiatric disorders and its actions in response to antidepressants will help us better understand brain development and quickly identify new therapeutic targets for the treatment of these mental illnesses.
Asunto(s)
Trastornos Mentales , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Sirolimus/farmacología , Antidepresivos/farmacología , Trastornos Mentales/tratamiento farmacológicoRESUMEN
Chronic urticaria (CU) is characterized by persistent skin hives, redness, and itching, enhanced by immune dysregulation and inflammation. Our main objective is identifying key genes and molecular mechanisms of chronic urticaria based on bioinformatics. We used the Gene Expression Omnibus (GEO) database and retrieved two GEO datasets, GSE57178 and GSE72540. The raw data were extracted, pre-processed, and analyzed using the GEO2R tool to identify the differentially expressed genes (DEGs). The samples were divided into two groups: healthy samples and CU samples. We defined cut-off values of log2 fold change ≥1 and p < .05. Analyses were performed in the Kyoto Encyclopaedia of Genes and Genomes (KEGG), the Database for Annotation, Visualization and Integrated Discovery (DAVID), Metascape, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and CIBERSOFT databases. We obtained 1613 differentially expressed genes. There were 114 overlapping genes in both datasets, out of which 102 genes were up-regulated while 12 were down-regulated. The biological processes included activation of myeloid leukocytes, response to inflammations, and response to organic substances. Moreover, the KEGG pathways of CU were enriched in the Nuclear Factor-Kappa B (NF-kB) signaling pathway, Tumor Necrosis Factor (TNF) signaling pathway, and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway. We identified 27 hub genes that were implicated in the pathogenesis of CU, such as interleukin-6 (IL-6), Prostaglandin-endoperoxide synthase 2 (PTGS2), and intercellular adhesion molecule-1 (ICAM1). The complex interplay between immune responses, inflammatory pathways, cytokine networks, and specific genes enhances CU. Understanding these mechanisms paves the way for potential interventions to mitigate symptoms and improve the quality of life of CU patients.
Asunto(s)
Urticaria Crónica , Perfilación de la Expresión Génica , Humanos , Perfilación de la Expresión Génica/métodos , Calidad de Vida , Inflamación , Biología Computacional/métodosRESUMEN
INTRODUCTION: Osteoporosis leads to more serious consequences in men than in women, but less is known about its impacts on health-related quality of life (HRQoL) of men, and whether the anti-osteoporosis treatment can improve HRQoL of men with osteopenia/osteoprosis. METHODS: We enrolled men with primary osteoporosis and age-matched healthy controls. We collected medical history, serum levels of carboxyl-terminal type I collagen telopeptide, procollagen type I propeptides, and bone mineral density of patients. All patients and controls completed the short-form 36 (SF-36) questionnaires. Changes in HRQoL of osteopenia/osteoporosis men were prospectively evaluated after alendronate or zoledronic acid treatment. RESULTS: A total of 100 men with primary osteoporosis or osteopenia and 100 healthy men were included. The patients were divided into three subgroups: osteopenia (n = 35), osteoporosis (n = 39) and severe osteoporosis (n = 26). Men with osteoporosis or severe osteoporosis had impaired HRQoL in domains of physical health compared to healthy controls. HRQoL scores in physical health related domains of patients with severe osteoporosis were significantly lower compared to healthy controls, and were the poorest among the three subgroups of patients. Fragility fracture history was correlated with lower SF-36 scores about physical health. In 34 men with newly diagnosed osteoporosis receiving bisphosphonates treatment, HRQoL scores were significantly improved in domains of physical health after treatments. CONCLUSIONS: The HRQoL is significantly impaired in men with osteoporosis, and the more severe the osteoporosis, the poorer the HRQoL. Fragility fracture is an important influencing factor of deteriorated HRQoL. Bisphosphonates treatment is beneficial to improve HRQoL of osteopenia/osteoporosis men.
Asunto(s)
Enfermedades Óseas Metabólicas , Fracturas Óseas , Osteoporosis , Masculino , Humanos , Femenino , Difosfonatos/uso terapéutico , Calidad de Vida , Osteoporosis/tratamiento farmacológico , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Densidad ÓseaRESUMEN
Developing easily accessible descriptors is crucial but challenging to rationally design single-atom catalysts (SACs). This paper describes a simple and interpretable activity descriptor, which is easily obtained from the atomic databases. The defined descriptor proves to accelerate high-throughput screening of more than 700â graphene-based SACs without computations, universal for 3-5d transition metals and C/N/P/B/O-based coordination environments. Meanwhile, the analytical formula of this descriptor reveals the structure-activity relationship at the molecular orbital level. Using electrochemical nitrogen reduction as an example, this descriptor's guidance role has been experimentally validated by 13â previous reports as well as our synthesized 4â SACs. Orderly combining machine learning with physical insights, this work provides a new generalized strategy for low-cost high-throughput screening while comprehensive understanding the structure-mechanism-activity relationship.
RESUMEN
BACKGROUND: The reduction in androgen level gives rise to a decrease in bone mineral density (BMD) and muscle strength, but the exact mechanisms are unclear. We investigated the roles of novel cytokines of sclerostin and irisin on bone and muscle of orchiectomized rats. METHODS: Twenty 3-month-old male rats were randomized to receive sham or orchiectomy (ORX) operation. Rats were euthanized after 8 weeks of surgery, and serum levels of sclerostin and irisin were measured by enzyme-linked immunosorbent assay at baseline and execution. Grip strength was measured by a grip strength tester at baseline and before execution. BMD and bone microarchitecture were measured by microcomputed tomography. The samples of bone and muscle were harvested at execution. Bone biomechanics were measured by three-point bending tests and vertebral body indentation tests. Bone and muscle histological features were analyzed by hematoxylin and eosin stain, Von Kossa's stain and tartrate resistant acid phosphatase stain. Simple linear regression analyses were used to analyze the relationships between serum levels of sclerostin, irisin and grip strength and BMD of ORX rats. RESULTS: Serum sclerostin level increased from 279 ± 44 pg/mL to 586 ± 57 pg/mL since baseline to 8 weeks after ORX (P = 0.002), which was significantly higher than that in sham rats (406 ± 20 pg/mL at execution) (P = 0.012). Serum irisin level decreased from 4.12 ± 0.20 ng/mL to 3.55 ± 0.29 ng/mL since baseline to 8 weeks of ORX (P = 0.048), which was significantly lower than sham rats (4.84 ± 0.37 pg/mL at execution) (P = 0.013). Trabecular BMD, parameters of bone microarchitecture, bone strength, grip strength and the myofibers size of soleus muscles were significantly lower in ORX rats than in sham group. Grip strength was positively correlated with femoral trabecular BMD (r = 0.713, P < 0.001) and bone volume/total volume (r = 0.712, P < 0.001) in all rats. The serum sclerostin level was negatively correlated to femoral trabecular BMD (r = -0.508, P = 0.022) and grip strength (r = -0.492, P = 0.028). Serum irisin level was positively correlated with femoral trabecular BMD (r = 0.597, P = 0.005), but no obvious correlation was found between irisin level and muscle strength in all rats. CONCLUSIONS: Reduced BMD, impaired bone microarchitecture, weak strength of bone and muscle, and thin myofibers were induced by androgen deficiency of ORX rats. Serum sclerostin and irisin levels were significantly changed after ORX, which might be closely correlated with the occurrence of osteoporosis and sarcopenia in ORX rats.
Asunto(s)
Andrógenos , Fibronectinas , Animales , Masculino , Ratas , Densidad Ósea , Músculos , Microtomografía por Rayos XRESUMEN
Biosurfactants (BSs) are known for their remarkable properties, however, their commercial applications are hampered partly by the high production cost. To overcome this issue, a biosurfactant producing strain, Rhodotorula sp.CC01 was isolated using landfill leachate as nitrogen source, while olive oil was determined as the best sole carbon source. The BS produced by Rhodotorula sp.CC01 had oil displacement diameter of 19.90 ± 0.10 cm and could reduce the surface tension of water to 34.77 ± 0.63 mN/m. It was characterized as glycolipids by thin layer chromatography, FTIR spectra, and GC-MS analysis, with the critical micelle concentration of 70 mg/L. Meanwhile, the BS showed stability over a wide range of pH (2-12), salinity (0-100 g/L), and temperature (20-100 °C). During the cultivation process, BS was produced with a maximum rate of 163.33 mg L-1 h-1 and a maximum yield of 1360 mg/L at 50 h. In addition, the removal efficiency of NH4+-N reached 84.2% after 75 h cultivation with a maximum NH4+-N removal rate of 3.92 mg L-1 h-1. Moreover, Rhodotorula sp.CC01 has proven to be of great potential in remediating petroleum hydrocarbons, as revealed by chromogenic assays. Furthermore, genes related to nitrogen metabolism and glycolipid metabolism were found in this strain CC01 after annotating the genome data with KEGG database, such as narB, glycoprotein glucosyltransferase, acetyl-CoA C-acetyltransferase, LRA1, LRA3, and LRA4. The findings of this study prove a cost-effective strategy for the production of BS by yeast through the utilization of landfill leachate.
Asunto(s)
Petróleo , Rhodotorula , Contaminantes Químicos del Agua , Biodegradación Ambiental , Hidrocarburos/metabolismo , Nitrógeno/metabolismo , Petróleo/metabolismo , Rhodotorula/genética , Rhodotorula/metabolismo , Tensoactivos/metabolismo , Contaminantes Químicos del Agua/metabolismoRESUMEN
The electrochemical CO2 reduction (CO2 ER) to multi-carbon chemical feedstocks over Cu-based catalysts is of considerable attraction but suffers with the ambiguous nature of active sites, which hinder the rational design of catalysts and large-scale industrialization. This paper describes a large-scale simulation to obtain realistic CuZn nanoparticle models and the atom-level structure of active sites for C2+ products on CuZn catalysts in CO2 ER, combining neural network based global optimization and density functional theory calculations. Upon analyzing over 2000 surface sites through high throughput tests based on NN potential, two kinds of active sites are identified, balanced Cu-Zn sites and Zn-heavy Cu-Zn sites, both facilitating C-C coupling, which are verified by subsequent calculational and experimental investigations. This work provides a paradigm for the design of high-performance Cu-based catalysts and may offer a general strategy to identify accurately the atomic structures of active sites in complex catalytic systems.
RESUMEN
Single-atom catalysts (SACs) with atomically dispersed metals have emerged as a new class of heterogeneous catalysts and have attracted considerable interest because they offer 100% metal atom utilization and show excellent catalytic behavior compared with traditionally supported nano-particles. However, it is challenging to explore the active sites and catalytic mechanisms of SACs through common characterization methods due to the isolated single atoms. Therefore, employing theoretical calculations to determine the nature of SACs' active sites and the reaction mechanisms is particularly meaningful. This paper describes the nature of SACs by summarizing the diverse applications and properties of SACs, which starts from computational simulation on a couple of important applications of SACs. Then the distinctive and fundamental properties of SACs are discussed. At last, the challenges and future perspectives of computational calculations for SACs are outlined.
RESUMEN
Recent studies have indicated that Sirt1 plays critical roles in the suppression of inflammation, T cell activation, and differentiation of hematopoietic progenitor cells. Severe aplastic anemia (SAA) is an immune-mediated disease that is characterized by elevated cytotoxic lymphocytes and type 1 cytokines. As a negative effector cytokine, interferon gamma (IFNγ) takes part in aplastic anemia through its inhibitory effect on hematopoiesis. In this study, we investigated the role of Sirt1 in the regulation of IFNγ in patients with SAA. A significant decrease in relative SIRT1 (p< 0.05) and increase in IFNG (p< 0.05) expression levels was observed in the sorted CD8+T cells of SAA patients compared to the controls. There was a significant negative correlation (r = -0.53, p < 0.05) between SIRT1 and IFNG expression in SAA patients. SRT3025, a Sirt1 activator, was shown to significantly reduce IFNγ (p < 0.01) and elevate Sirt1 (p < 0.05) expression in the CD8+T cells of SAA patients, and also showed a therapeutic role in an aplastic anemia mouse model. In conclusion, the defective Sirt1 may be correlated to the abnormal IFNγ expression in SAA patients, and activation of Sirt1 signaling may help improve the inflammatory status of SAA.
Asunto(s)
Anemia Aplásica/sangre , Linfocitos T CD8-positivos/metabolismo , Interferón gamma/sangre , Sirtuina 1/sangre , Adulto , Anciano , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/patología , Anilidas/farmacología , Animales , Linfocitos T CD8-positivos/patología , Activadores de Enzimas/farmacología , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Tiazoles/farmacologíaRESUMEN
The author describe a method for preparation of green fluorescent nitrogen-doped carbon dots (N-CDs) through hydrothermal treatment of a mixture of lotus leaf juice and ethylenediamine (EDA). The N-CDs have uniform size, good dispersibility and water solubility. Under 316 and 366 nm photoexcitation, they show dual fluorescence with emission peaks at 415 and 509 nm, respectively. They are positively charge and display low cytotoxicity. This makes them an excellent choice for fluorometric assays and for bioimaging. A ratiometric assay was developed for the determination of the activity of acid phosphatase (ACP). It is based on the aggregation- induced quenching (AIQ) of the fluorescence of the N-CDs by sodium hexametaphosphate (NaPO3)6. Enzymatic hydrolysis of (NaPO3)6 by ACP leads to the disintegration of (NaPO3)6 and to the restoration of fluorescence. The measurement of the ratio of fluorescence at two wavelengths (415 and 509 nm), background interference and fluctuating signals can be widely eliminated. The method works in the 1-50 U·L-1 ACP activity range and has a detection limit of 0.43 U·L-1. It was successfully applied (a) to the determination of ACP in spiked serum samples, (b) to ACP inhibitor screening, and (c) to imaging of ACP in HePG2 cells. Graphical abstract Schematic presentation of the synthesis of nitrogen-doped carbon dots (N-CDs), and their application to the ratiometric fluorometric determination of acid phosphatase (ACP) based on the aggregation-induced quenching and enzymatic hydrolysis.
Asunto(s)
Fosfatasa Ácida , Carbono/química , Colorantes Fluorescentes/química , Nitrógeno/química , Fosfatasa Ácida/análisis , Fosfatasa Ácida/antagonistas & inhibidores , Fosfatasa Ácida/sangre , Fosfatasa Ácida/química , Tecnología Química Verde , Células Hep G2 , Humanos , Lotus , Fosfatos/química , Extractos Vegetales/química , Hojas de la PlantaRESUMEN
Chlamydia trachomatis is one of the most prevalent sexually transmitted pathogens. There is currently no commercially available vaccine against C. trachomatis. Chlamydial translocated actin-recruiting phosphoprotein (Tarp) can induce cellular and humoral immune responses in murine models and has been regarded as a potential vaccine candidate. In this report, the amino acid sequence of Tarp was analyzed using computer-assisted techniques to scan B-cell epitopes, and six possible linear B-cell epitopes peptides (aa80-95, aa107-123, aa152-170, aa171-186, aa239-253 and aa497-513) with high predicted antigenicity and high conservation were investigated. Sera from mice immunized with these potential immunodominant peptides was analyzed by ELISA, which showed that epitope 152-170 elicited serum immunoglobulin G (IgG) response and epitope 171-186 elicited both serum IgG and mucosal secretory immunoglobulin A response. The response of immune sera of epitope 171-186 to endogenous Tarp antigen obtained from the Hela229 cells infected with C. trachomatis was confirmed by Western blot and indirect fluorescence assay. In addition, binding of the antibodies against epitope 171-186 to endogenous Tarp was further confirmed by competitive ELISA. Our results demonstrated that the putative epitope (aa171-186) was an immunodominant B-cell epitope of Tarp. If proven protective and safe, this epitope, in combination with other well-documented epitopes, might be included into a candidate epitope-based vaccine against C. trachomatis.
Asunto(s)
Linfocitos B/química , Proteínas Bacterianas/química , Chlamydia trachomatis/química , Epítopos/química , Secuencia de Aminoácidos , Animales , Linfocitos B/inmunología , Ensayo de Inmunoadsorción Enzimática , Epítopos/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Ratones , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
We evaluated the immunogenicity and efficacy of a candidate vaccine comprising the major outer membrane protein (MOMP) multi-epitope of Chlamydia trachomatis. A short gene of multi-epitope derived from MOMP containing multiple T- and B-cell epitopes was artificially synthesized. The recombinant plasmid pET32a(+) containing codon optimized MOMP multi-epitope gene was constructed. Expression of the fusion protein Trx-His-MOMP multi-epitope in Escherichia coli was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis. Balb/c mice were inoculated with the purified fusion protein subcutaneously three times with 2-week intervals. Results showed that the MOMP multi-epitope elicited not only strong humoral immune responses to C. trachomatis by generating significantly high levels of specific antibodies (IgG1 and IgG2a), but also a cellular immune response by inducing robust cytotoxic T lymphocyte responses in mice. Furthermore, the MOMP multi-epitope substantially primed secretion of IFN-γ, revealing that this vaccine could induce a strong Th1 response. Finally, the mice vaccinated with the MOMP multi-epitope displayed a reduction of C. trachomatis shedding upon a chlamydial challenge and an accelerated clearance of the infected C. trachomatis. In conclusion, the MOMP multi-epitope vaccine may have the potentiality for the development of effective prophylactic and therapeutic vaccines against the C. trachomatis infection.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas Bacterianas/inmunología , Chlamydia trachomatis/inmunología , Epítopos/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/biosíntesis , Epítopos/química , Femenino , Genitales/microbiología , Interferón gamma/sangre , Interleucina-4/sangre , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Correction for 'High-performance p-i-n perovskite photodetectors and image sensors with long-term operational stability enabled by a corrosion-resistant titanium nitride back electrode' by Tian Sun et al., Nanoscale, 2023, 15, 7803-7811, https://doi.org/10.1039/D3NR00410D.
RESUMEN
OBJECTIVE: Deficiency of cartilage-associated protein (CRTAP) can cause extremely rare autosomal recessive osteogenesis imperfecta (OI) type VII. We investigated the pathogenic mechanisms of CRTAP variants through functional studies on bones of patients with OI. METHODS: Two nonconsanguineous families with CRTAP mutations were included and their phenotypes and genotypes were evaluated. Bone specimens were obtained from 1 patient with OI and a normal control during orthopedic surgery. The impacts of the novel variant on the CRTAP transcript were confirmed. The expression levels of CRTAP mRNA and CRTAP protein were analyzed. The quantification of prolyl 3-hydroxylation in the α1 chain of type I collagen was evaluated. RESULTS: Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities. The c.621 + 1G > A and c.1153-3C > G mutations were identified in CRTAP in the patients with OI. The c.621 + 1G > A variant was a novel mutation that could impair mRNA transcription, leading to a truncated CRTAP protein. In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was simultaneously accompanied by significantly reduced prolyl 3-hydroxylation at Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone. CONCLUSION: The novel c.621 + 1G > A mutation in CRTAP expands the genotypic spectrum of type VII OI. Biallelic mutations of c.621 + 1G > A and c.1153-3C > G in CRTAP can lead to reduced CRTAP mRNA and deficient CRTAP protein in osteoblasts, which reduces 3-hydroxylation in Pro986 of the α1 chain of type I collagen and impairs bone formation, thus contributing to severe OI type VII.
Asunto(s)
Proteínas de la Matriz Extracelular , Chaperonas Moleculares , Osteogénesis Imperfecta , Fenotipo , Humanos , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/patología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Masculino , Femenino , Chaperonas Moleculares/genética , Mutación , Niño , Linaje , Preescolar , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Genotipo , Osteoblastos/metabolismo , Osteoblastos/patología , Cadena alfa 1 del Colágeno Tipo I , Adulto , AdolescenteRESUMEN
Leukemia is a widespread hematological malignancy characterized by an elevated white blood cell count in both the blood and the bone marrow. Despite notable advancements in leukemia intervention in the clinic, a large proportion of patients, especially acute leukemia patients, fail to achieve long-term remission or complete remission following treatment. Therefore, leukemia therapy necessitates optimization to meet the treatment requirements. In recent years, a multitude of materials have undergone rigorous study to serve as delivery vectors or direct intervention agents to bolster the effectiveness of leukemia therapy. These materials include liposomes, protein-based materials, polymeric materials, cell-derived materials, and inorganic materials. They possess unique characteristics and are applied in a broad array of therapeutic modalities, including chemotherapy, gene therapy, immunotherapy, radiotherapy, hematopoietic stem cell transplantation, and other evolving treatments. Here, an overview of these materials is presented, describing their physicochemical properties, their role in leukemia treatment, and the challenges they face in the context of clinical translation. This review inspires researchers to further develop various materials that can be used to augment the efficacy of multiple therapeutic modalities for novel applications in leukemia treatment.
Asunto(s)
Leucemia , Humanos , Leucemia/terapia , Animales , Liposomas/química , Polímeros/química , Materiales Biocompatibles/química , Antineoplásicos/uso terapéutico , Antineoplásicos/químicaRESUMEN
CONTEXT: The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. OBJECTIVE: To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. METHODS: This was a prospective, open-label study. Patients were randomized to receive denosumab 60â mg every 6 months or zoledronic acid 5â mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated. RESULTS: A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of ß-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group. CONCLUSION: Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.
Asunto(s)
Conservadores de la Densidad Ósea , Densidad Ósea , Denosumab , Osteogénesis Imperfecta , Ácido Zoledrónico , Humanos , Denosumab/uso terapéutico , Denosumab/efectos adversos , Denosumab/administración & dosificación , Ácido Zoledrónico/uso terapéutico , Ácido Zoledrónico/administración & dosificación , Ácido Zoledrónico/efectos adversos , Femenino , Masculino , Adulto , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis Imperfecta/genética , Densidad Ósea/efectos de los fármacos , Estudios Prospectivos , Resultado del Tratamiento , Remodelación Ósea/efectos de los fármacos , Adulto Joven , Persona de Mediana EdadRESUMEN
Background: At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Methods: Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. Results: In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. Conclusions: The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.
RESUMEN
CONTEXT: Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. OBJECTIVE: We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid. METHODS: In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment. RESULTS: After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of denosumab, of which 14.3% reached hypercalcemic crisis. Rebound hypercalcemia could be alleviated by switching to zoledronic acid treatment. CONCLUSION: Treatment with denosumab or zoledronic acid is beneficial in increasing BMD and improving the spinal morphometry of children with OI. However, denosumab should be used with caution in pediatric patients with OI because of its common and dangerous side effect of rebound hypercalcemia. The appropriate dosage and dosing interval of denosumab need to be further explored in children with OI.
Asunto(s)
Conservadores de la Densidad Ósea , Densidad Ósea , Denosumab , Osteogénesis Imperfecta , Ácido Zoledrónico , Humanos , Denosumab/uso terapéutico , Denosumab/efectos adversos , Denosumab/administración & dosificación , Osteogénesis Imperfecta/tratamiento farmacológico , Niño , Femenino , Masculino , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Conservadores de la Densidad Ósea/efectos adversos , Conservadores de la Densidad Ósea/administración & dosificación , Ácido Zoledrónico/uso terapéutico , Ácido Zoledrónico/efectos adversos , Ácido Zoledrónico/administración & dosificación , Preescolar , Adolescente , Estudios Prospectivos , Resultado del Tratamiento , Remodelación Ósea/efectos de los fármacosRESUMEN
M1/M2 polarization transitions of microglial phenotypes determine the states of neuroinflammation, which is critical in the pathophysiology of diabetic encephalopathy. This study aims to investigate the effects of advanced glycation end products (AGEs) on the microglial polarization state, the role of miR-146a-5p in the regulation of microglial polarization, and the underlying signaling pathways. BV-2 cells were incubated with N-ε-carboxymethyl lysine (CML), one kind of Advanced Glycation End Products (AGEs), to induce polarization. CD11b and iNOS and CD206 and Arg-1 were used to evaluate M1 and M2 microglia, respectively. The mRNA and protein expression levels of miR-146a-5p, transcription factor NF-κB, and inflammasome NLRP3 were measured. High and low expression of miR-146a-5p in the BV-2 cell line was generated by lentivirus transfection technology. RAGE, TLR-4, and NF-κB antagonists were applied to evaluate the underlying signaling pathways. Compared with the control group, CML upregulated the M1 phenotype and downregulated the M2 phenotype. These effects were reversed by overexpression of miR-146a. Furthermore, the expression of inflammasome NLRP3 and NF-κB was upregulated in the CML group and was reduced after miR-146a overexpression. And then overexpression of miR-146a effects was reversed by inhibition miR-146a expression. An NF-κB antagonist (PDTC), a RAGE antagonist (FPS-ZMI), and a TLR-4 antagonist (TLI-095) all reversed the polarization state induced by CML. In summary, CML induced polarization transitions to M1 phenotype and promoted inflammasome NLRP3 expression in BV-2 cells. The RAGE or TLR-4/miR-146a/NLRP3/NF-кB pathway might participate in the regulation of CML-induced BV-2 polarization.