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Brassinosteroids (BRs) are phytohormones that regulate stomatal development. In this study, we report that BR represses stomatal development in etiolated Arabidopsis (Arabidopsis thaliana) cotyledons via transcription factors BRASSINAZOLE RESISTANT 1 (BZR1) and bri1-EMS SUPPRESSOR1 (BES1), which directly target MITOGEN-ACTIVATED PROTEIN KINASE KINASE 9 (MKK9) and FAMA, 2 important genes for stomatal development. BZR1/BES1 bind MKK9 and FAMA promoters in vitro and in vivo, and mutation of the BZR1/BES1 binding motif in MKK9/FAMA promoters abolishes their transcription regulation by BZR1/BES1 in plants. Expression of a constitutively active MKK9 (MKK9DD) suppressed overproduction of stomata induced by BR deficiency, while expression of a constitutively inactive MKK9 (MKK9KR) induced high-density stomata in bzr1-1D. In addition, bzr-h, a sextuple mutant of the BZR1 family of proteins, produced overabundant stomata, and the dominant bzr1-1D and bes1-D mutants effectively suppressed the stomata-overproducing phenotype of brassinosteroid insensitive 1-116 (bri1-116) and brassinosteroid insensitive 2-1 (bin2-1). In conclusion, our results revealed important roles of BZR1/BES1 in stomatal development, and their transcriptional regulation of MKK9 and FAMA expression may contribute to BR-regulated stomatal development in etiolated Arabidopsis cotyledons.
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Proteínas de Arabidopsis , Arabidopsis , Brassinosteroides , Cotilédone , Proteínas de Ligação a DNA , Regulação da Expressão Gênica de Plantas , Proteínas Nucleares , Estômatos de Plantas , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Brassinosteroides/metabolismo , Estômatos de Plantas/crescimento & desenvolvimento , Estômatos de Plantas/genética , Estômatos de Plantas/efeitos dos fármacos , Cotilédone/genética , Cotilédone/crescimento & desenvolvimento , Cotilédone/metabolismo , Cotilédone/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Mutação/genética , Regiões Promotoras Genéticas/genética , Estiolamento , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Ligação Proteica/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genéticaRESUMO
Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.
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Neoplasias da Mama , Humanos , Feminino , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Trastuzumab/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Fosforilação , Fator de Transcrição AP-2/metabolismo , Receptor ErbB-2/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Quinases da Família src/metabolismo , Quinases da Família src/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tirosina/metabolismo , Tirosina/uso terapêuticoRESUMO
The aim of the present study was to explore the molecular mechanisms by which miR-193b-3p-trans-fected bone marrow mesenchymal stem cells (BMSCs) transplantation improves neurological impairment after traumatic brain injury (TBI) through sphingosine-1-phosphate receptor 3 (S1PR3)-mediated regulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway at the cellular and animal levels. BMSCs were transfected with miR-193b-3p. A TBI cell model was established by oxygen-glucose deprivation (OGD)-induced HT22 cells, and a TBI animal model was established by controlled cortical impact (CCI). Cell apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL), and cell activity was detected by a cell counting kit 8 (CCK-8) assay. Western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of related proteins and genes. In this study, transfection of miR-193b-3p into BMSCs significantly enhanced BMSCs proliferation and differentiation. Transfection of miR-193b-3p reduced the levels of the interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-alpha (TNF-α) inflammatory factors in cells and mouse models, and it inhibited neuronal apoptosis, which alleviated OGD-induced HT22 cell damage and neural function damage in TBI mice. Downstream experiments showed that miR-193b-3p targeting negatively regulated the expression of S1PR3, promoted the activation of the PI3K/AKT/mTOR signaling pathway, and inhibited the levels of apoptosis and inflammatory factors, which subsequently improved OGD-induced neuronal cell damage and nerve function damage in TBI mice. However, S1PR3 overexpression or inhibition of the PI3K/AKT/mTOR signaling pathway using the IN-2 inhibitor weakened the protective effect of miR-193b-3p-transfected BMSCs on HT22 cells. Transplantation of miR-193b-3p-transfected BMSCs inhibits neurological injury and improves the progression of TBI in mice through S1PR3-mediated regulation of the PI3K/AKT/mTOR pathway.
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Lesões Encefálicas Traumáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores de Esfingosina-1-Fosfato , Serina-Treonina Quinases TOR , Animais , Humanos , Masculino , Camundongos , Apoptose , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/terapia , Modelos Animais de Doenças , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Optimizing the electrode/electrolyte interface structure is the key to realizing high-voltage Li-metal batteries (LMBs). Herein, a functional electrolyte is introduced to synergetically regulate the interface layer structures on the high-voltage cathode and the Li-metal anode. Saccharin sodium (NaSH) as a multifunctional electrolyte additive is employed in fluorinated solvent-based electrolyte (FBE) for robust interphase layer construction. On the one hand, combining the results of ex-situ techniques and in-situ electrochemical dissipative quartz crystal microbalance (EQCM-D) technique, it can be seen that the solid electrolyte interface (SEI) layer constructed by NaSH-coupled fluoroethylene carbonate (FEC) on Li-metal anode significantly inhibits the growth of lithium dendrites and improves the cyclic stability of the anode. On the other hand, the experimental results also confirm that the cathode-electrolyte interface (CEI) layer induced by NaSH-coupled FEC effectively protects the active materials of LiCoO2 and improves their structural stability under high-voltage cycling, thus avoiding the material rupture. Moreover, theoretical calculation results show that the addition of NaSH alters the desolvation behavior of Li+ and enhances the transport kinetics of Li+ at the electrode/electrolyte interface. In this contribution, the LiCoO2ÇLi full cell containing FBE+NaSH results in a high capacity retention of 80% after 530 cycles with a coulombic efficiency of 99.8%.
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AIM: We aimed to assess the global implications of low physical activity (LPA) on type 2 diabetes mellitus (T2DM) by utilizing data from the Global Burden of Disease (GBD) 2019. METHODS: The analysis was conducted by examining the age-standardized disability-adjusted life years (DALYs) rates over a 30-year period. To assess the trends, we utilized estimated annual percentage changes (EAPCs). RESULTS: The study revealed a notable increase in the burden of DALYs attributable to T2DM resulting from LPA, with an EAPC of 0.84 (95% confidence interval 0.78-0.89). Among the regions examined, Oceania showed the highest burden, whereas Eastern Europe exhibited the lowest burden. Specifically, within the Central Asia region, a considerable increase in T2DM-LPA DALYs was observed, with an EAPC of 3.18 (95% confidence interval 3.01-3.36). The burden associated with T2DM-LPA DALYs was found to be similar between genders and increased across all age groups, peaking in the 80-84 years. Furthermore, there was a clear association between the socio-demographic index (SDI) and the age-standardized DALYs rate. Regions categorized as low-middle and middle SDI experienced a substantial rise in burden. CONCLUSION: This study highlights a substantial increase in the T2DM-LPA DALYs in low-middle and middle SDI regions, as well as among individuals aged 80-84 years. These findings emphasize the importance of implementing comprehensive global health interventions that promote physical activity, particularly targeting high-risk populations and regions.
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Diabetes Mellitus Tipo 2 , Exercício Físico , Carga Global da Doença , Saúde Global , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Adulto , Anos de Vida Ajustados por Deficiência , Comportamento Sedentário , Adulto Jovem , Oceania/epidemiologiaRESUMO
BACKGROUND: Lysimachia christinae Hance (LCH) is a traditional medicine used to treat gallstone disease and cholecystitis. Despite its known anti-inflammatory and choleretic effects, its quality has not been extensively evaluated. OBJECTIVE: In this study, we aimed to establish a reliable quality evaluation method for LCH via fingerprint, spectrum-effect relationship, and quantitative analyses of multicomponents by a single marker (QAMS). METHODS: First, the fingerprints and anti-inflammatory and choleretic activities of 14 LCH batches were determined. Then, the gray relation analysis method was used to analyze the peak areas of the fingerprint profile and pharmacodynamic data. Subsequently, the characteristic peaks were tentatively identified using high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Finally, rutin was selected as the internal reference material, and QAMS was used to analyze the LCH components. RESULTS: Pharmacodynamic experiments confirmed that LCH exerted anti-inflammatory and choleretic effects. Moreover, 15 flavonoids related to the anti-inflammatory and choleretic effects of LCH were identified. Notably, relative error percentage between the QAMS and external standard method was less than 5%. CONCLUSION: This study successfully established a comprehensive evaluation method for the qualitative and quantitative analyses of LCH.
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Lysimachia , Animais , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/análise , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/análise , Lysimachia/química , Controle de Qualidade , Feminino , CamundongosRESUMO
Background: The increasing geriatric population and variation in the disease spectrum among older adults in China contribute to a growing demand for more aged adult care in Chinese society. Relevant studies have shown that living arrangements with various family members have variable impacts on the older adult's health. This study employs the Frailty Index as a unified measurement standard to assess the overall health levels, integrating the specific "in-law relationships" into the research on living arrangements and the health of older adults. Methods: This study used data from the China Longitudinal Aging Social Survey 2016-2018. OLS and Quantile Regression were used to investigate the in-law relationship on older adult health and whether this impact is homogeneous across older individuals with varying infirmity levels. The study used a lag model and propensity score matching to compensate for potential endogeneity concerns. Results: The study found that residing with a daughter-in-law (20.22%) had a significant positive correlation with the frailty index (ß=0.0088, Pï¼0.001), indicating that the relationship between parents-in-law and daughters-in-law can influence the health of the older adult. This impact is nonlinear and non-homogeneous for older adult people with various levels of frailty, exhibiting an approximately decreasing and then increasing U-shaped distribution, which denotes that older adult people with different health conditions have distinct demands for intergenerational care. In addition, this impact varies among older adult groups of disparate genders, urban and rural areas, and age groups. Conclusion: This study investigates the impact of "in-law relationships" within living arrangements on the health of older adults. It shows that co-residing with a daughter-in-law has adverse effects on the health of older adults. Therefore, the study suggests that when the health and economic conditions of the elderly permit, a "live-near-but-not-with" living arrangement with their children can be considered.
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Purpose: To evaluate the burden of type 2 diabetes (T2D) among adolescents (15-24 years old) from 1990 to 2019. Methods: The age-standardized incidence rate (ASIR) and disability-adjusted life years (DALYs) rate of adolescents were analyzed according to age, sex, geographical location, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) was estimated to quantify the trends. Results: From 1990 to 2019, the ASIR (EAPC = 1.07) and age-standardized DALY rate (EAPC = 2.01) of T2D in adolescents showed an increasing trend. The ASIR was higher in males than in females. The burden was greater in the 20-24-year age group. Of the five SDI regions, the highest ASIR and age-standardized DALY rate were found in low-middle-SDI regions, while the greatest increase in these rates was observed in high-SDI regions (EAPC = 3.28 and 3.55, respectively). Of the 21 regions analyzed, the highest ASIR and age-standardized DALY rate were found in Oceania. Of the 204 countries analyzed, the Marshall Islands (651.16) and Kiribati (277.42) had the highest ASIR and DALYs, respectively. The regions with the greatest increase in the ASIR from 1990 to 2019 were Western Europe (EAPC = 4.15), high-income North America (EAPC = 4.72). Conclusions: The global burden of T2D in adolescents showed an overall upward trend from 1990 to 2019. It is necessary to strengthen prevention measures related to risk factors for T2D among young people, especially in areas with a low-to-medium SDI.
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Diabetes Mellitus Tipo 2 , Saúde Global , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Masculino , Feminino , Adulto Jovem , Incidência , Anos de Vida Ajustados por Deficiência/tendências , Efeitos Psicossociais da Doença , Carga Global da Doença/tendênciasRESUMO
Background: Hip fractures, commonly known as the "terminal fracture of life," frequently necessitate prompt surgical intervention and are accompanied by significant perioperative pain. Objective: This investigation was performed to assess the impact of fascia iliaca compartment block (FICB) on heart rate variability during the perioperative period in elderly individuals with hip fractures. Design: Single-center, randomized, controlled clinical trial. Setting: The study was conducted from September 2021 to February 2023 at one tertiary care hospital in China. Participants: Patients aged ≥60 years who underwent general anesthesia for hip fracture surgery were screened for enrollment. Eighty patients were initially assessed for eligibility, 70 underwent randomization, and 62 were included in the final analysis. Methods: Preoperatively, the patients were randomly allocated to either receive (Group F) or not receive (Group C) ultrasound-guided suprainguinal FICB. The primary endpoint was heart rate variability indicators at the corresponding time points. The secondary endpoints included the mean arterial pressure and heart rate measured at different time points [upon admission to the operating room (T1), during positioning (T2), at the time of skin incision (T3), 30 min after the start of surgery (T4), and 6 h postoperatively (T5)] and visual analogue scale (VAS) score, dose of oral pain medication over 24 h, and satisfaction scores were valued. Results: Compared with Group C, Group F had a significantly reduced low-frequency band, high-frequency band, and low-/high-frequency band ratio at T3, T4, and T5 (P < 0.05). Group F also had a lower heart rate at T2, T3, T4, and T5 (P < 0.05). Moreover, Group F had lower flurbiprofen dosages at 24 h postoperatively (P < 0.05) and lower resting VAS scores at 6 and 24 h postoperatively (P < 0.05). Conclusion: Utilization of ultrasound-guided FICB has the potential to yield efficacious analgesic effects, mitigate the pronounced fluctuations in heart rate induced by surgical stimulation, and maintain autonomic function stability to a certain degree.
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Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.
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Catalytic mechanism-based, light-activated traps have recently been developed to identify the substrates of cysteine or serine hydrolases. These traps are hydrolase mutants whose catalytic cysteine or serine are replaced with genetically encoded 2,3-diaminopropionic acid (DAP). DAP-containing hydrolases specifically capture the transient thioester- or ester-linked acyl-enzyme intermediates resulting from the first step of the proteolytic reaction as their stable amide analogs. The trapped substrate fragments allow the downstream identification of hydrolase substrates by mass spectrometry and immunoblotting. In this protocol, we provide a detailed step-by-step guide for substrate capture and identification of the peptidase domain of the large tegument protein deneddylase (UL36USP) from human herpesvirus 1, both in mammalian cell lysate and live mammalian cells. Four procedures are included: Procedure 1, DAP-mediated substrate trapping in mammalian cell lysate (~8 d); Procedure 2, DAP-mediated substrate trapping in adherent mammalian cells (~6 d); Procedure 3, DAP-mediated substrate trapping in suspension mammalian cells (~5 d); and Procedure 4, substrate identification and validation (~12-13 d). Basic skills to perform protein expression in bacteria or mammalian cells, affinity enrichment and proteomic analysis are required to implement the protocol. This protocol will be a practical guide for identifying substrates of serine or cysteine hydrolases either in a complex mixture, where genetic manipulation is challenging, or in live cells such as bacteria, yeasts and mammalian cells.
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Optimizing the pore structure and its interaction with the electrolytes was vital for enhancing the performance of supercapacitors based on the electrical double layer mechanism. In this study, graded porous carbon material (STP) with outstanding properties was prepared by adjusting the activation temperature and KOH dosage in the microwave pyrolysis process of sargassum thunbergii. The results demonstrated that better electrochemical performance was obtained when 1 M NaNO3 was used as electrolyte and STP-800-3 was employed as electrode material, attributed to its excellent specific surface area (SSA) of 2011.8 m2 g-1, high micropore ratio, and the optimal matching degree between micropore size and electrolyte ion diameter. Moreover, the operating voltage window was expanded to 2.0 V in supercapacitors assembled with 6 M NaNO3 high-concentration electrolyte. Simultaneously, the symmetric supercapacitors exhibited a remarkable specific capacitance of 290.0 F g-1, a high energy density of 39.0 W h kg-1, and outstanding capacity retention at 70.9% after 10,000 charge/discharge cycles based on 6 M NaNO3 electrolyte. Consequently, the results provided valuable technical support and theoretical basis to foster progress of novel and high-performance supercapacitors.
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This was a single-centre retrospective study. Minimally invasive techniques for transforaminal lumbar interbody fusion (MIS-TLIF), oblique lumbar interbody fusion (OLIF), and percutaneous endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) have been extensively used for lumbar degenerative diseases. The present study analyses the short-term and mid-term clinical effects of the above three minimally invasive techniques on L4/L5 degenerative spondylolisthesis. In this retrospective study, 98 patients with L4/L5 degenerative spondylolisthesis received MIS-TLIF, 107 received OLIF, and 114 received Endo-TLIF. All patients were followed up for at least one year. We compared patient data, including age, sex, body mass index (BMI), Oswestry disability index (ODI), visual analogue scale of low back pain (VAS-B), visual analogue scale of leg pain (VAS-L), surgical time, blood loss, drainage volume, hospital stay, complications, and neurological status. Moreover, we performed imaging evaluations, including lumbar lordosis angle (LLA), disc height (DH) and intervertebral fusion status. No significant differences were noted in age, sex, BMI, preoperative ODI, preoperative VAS-B, preoperative VAS-L, preoperative LLA, or preoperative DH. Patients who underwent OLIF had significantly decreased blood loss, a lower drainage volume, and a shorter hospital stay than those who underwent MIS-TLIF or Endo-TLIF (P < 0.05). The VAS-B in the OLIF group significantly decreased compared with in the MIS-TLIF and Endo-TLIF groups at 6 and 12 months postoperatively (P < 0.05). The VAS-L in the Endo-TLIF group significantly decreased compared with that in the MIS-TLIF and OLIF groups at 6 months postoperatively (P < 0.05). The ODI in the OLIF group was significantly better than that in the MIS-TLIF and Endo-TLIF groups at 6 months postoperatively (P < 0.05). No statistically significant differences in the incidence of complications and healthcare cost were found among the three groups. Follow-up LLA and DH changes were significantly lower in the OLIF group than in the other groups (P < 0.05). The intervertebral fusion rate was significantly higher in the OLIF group than in the other groups at 6 and 12 months postoperatively (P < 0.05). In conclusion, while MIS-TLIF, OLIF, and Endo-TLIF techniques can effectively treat patients with L4/5 degenerative spondylolisthesis, OLIF has more benefits, including less operative blood loss, a shorter hospital stay, a smaller drainage volume, efficacy for back pain, effective maintenance of lumbar lordosis angle and disc height, and a higher fusion rate. OLIF should be the preferred surgical treatment for patients with L4/5 degenerative spondylolisthesis.
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Lordose , Fusão Vertebral , Espondilolistese , Humanos , Estudos Retrospectivos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Resultado do Tratamento , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Espondilolistese/diagnóstico por imagem , Espondilolistese/cirurgia , Lordose/cirurgia , Fusão Vertebral/métodosRESUMO
The blood-brain barrier (BBB) is pivotal in maintaining neuronal physiology within the brain. This review delves into the alterations of the BBB specifically in the context of geriatric epilepsy. We examine how age-related changes in the BBB contribute to the pathogenesis of epilepsy in the elderly and present significant challenges in pharmacotherapy. Subsequently, we evaluate recent advancements in drug delivery methods targeting the BBB, as well as alternative approaches that could bypass the BBB's restrictive nature. We particularly highlight the use of neurotropic viruses and various synthetic nanoparticles that have been investigated for delivering a range of antiepileptic drugs. Additionally, the advantage and limitation of these diverse delivery methods are discussed. Finally, we analyze the potential efficacy of different drug delivery approaches in the treatment of geriatric epilepsy, aiming to provide insights into more effective management of this condition in the elderly population.
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Waterfowl astroviruses are mainly duck astroviruses and goose astroviruses, of which duck astroviruses (DAstV-3, -4), goose astroviruses (GoAstV-1, -2) are the four new waterfowl 21 astroviruses in recent years, which can lead to enteritis, viral hepatitis, gout and reduce the growth performance of waterfowl, affecting the healthy development of the waterfowl farming industry. Since no targeted drugs or vaccines on the market, studies on the epidemiology of the virus are necessary for vaccine development. In this study, we collected 1546 waterfowl samples from 13 provinces in China for epidemiological investigation. The results showed that 260 samples (16.8%) were positive. Four species of astrovirus were detected in 13 provinces except Fujian province. Among the four sites tested, the highest positive rates were found in farms and slaughterhouses. Cross-host and mixed infection were observed in four species of waterfowl astroviruses. The whole genome of 17 isolates was sequenced and compared with published sequences. Genetic evolution and homology analysis showed that the isolated strains had high similarity to their reference sequences. To assess the pathogenicity of GoAstV, 7-day-old goslings were inoculated with GoAstV-1 and GoAstV-2 by the intramuscular route, and infected geese showed similar clinical signs, such as anorexia, depression, and weight loss. Organ damage was seen after infection, with histopathological changes in the heart, liver, spleen, kidney, and intestine, and higher viral loads in throat and anal swabs. These findings increase our understanding of the pathogenicity of GoAstV-1 and GoAstV-2 in goslings and provide more references for future research.
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Background: Acute myocardial infarction (AMI) is a common cardiovascular disease in clinic. Currently, there is no specific treatment for AMI. Carbon dots (CDs) have been reported to show excellent biological activities, which hold promise for the development of novel nanomedicines for the treatment of cardiovascular diseases. Methods: In this study, we firstly prepared CDs from the natural herb Curcumae Radix Carbonisata (CRC-CDs) by a green, simple calcination method. The aim of this study is to investigate the cardioprotective effect and mechanism of CRC-CDs on isoproterenol (ISO) -induced myocardial infarction (MI) in rats. Results: The results showed that pretreatment with CRC-CDs significantly reduced serum levels of cardiac enzymes (CK-MB, LDH, AST) and lipids (TC, TG, LDL) and reduced st-segment elevation and myocardial infarct size on the ECG in AMI rats. Importantly, cardiac ejection fraction (EF) and shortening fraction (FS) were markedly elevated, as was ATPase activity. In addition, CRC-CDs could significantly increase the levels of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in myocardial tissue, thereby exerting cardioprotective effect by enhancing the antioxidant capacity of myocardial tissue. Moreover, the TUNEL staining image showed that positive apoptotic cells were markedly declined after CRC-CDs treatment, which indicate that CRC-CDs could inhibit cardiomyocyte apoptosis. Importantly, The protective effect of CRC-CDs on H2O2 -pretreated H9c2 cells was also verified in vitro. Conclusion: Taken together, CRC-CDs has the potential for clinical application as an anti-myocardial ischemia drug candidate, which not only provides evidence for further broadening the biological application of cardiovascular diseases, but also offers potential hope for the application of nanomedicine to treat intractable diseases.
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Infarto do Miocárdio , Isquemia Miocárdica , Animais , Ratos , Peróxido de Hidrogênio , Infarto do Miocárdio/tratamento farmacológico , Miocárdio , CarbonoRESUMO
CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory-like (TCM-like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM-like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated TCM-like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhighACElow) mainly contributes to TCM-like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.
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Linfócitos T CD8-Positivos , Monócitos , Linfócitos T CD8-Positivos/imunologia , Camundongos , Animais , Monócitos/imunologia , Humanos , Células T de Memória/imunologia , Memória Imunológica/imunologia , Modelos Animais de Doenças , Neoplasias/imunologia , Neoplasias/terapia , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Imunoterapia Adotiva/métodosRESUMO
Biochar with adjustable redox activity is an effective strategy for immobilization of excess arsenic (As(III)) contaminated soil. However, biochar exhibits limitations in terms of electron transfer efficiency and immobilization efficiency due to insufficient activation energy. In this study, As(III) in the soil was rapidly immobilized by adding magnetic biochar (Fe-BC) and introducing microwave irradiation energy to enhance electron transport efficiency. The results showed that the pore structure and iron species (ZVI, Fe3O4) loaded onto the biochar could be modulated by controlling the temperature and time of microwave pyrolysis, which enhanced the microwave absorption capacity and the immobilization performance of As. After adding Fe-BC (10 wt%) and treating with microwave irradiation for 3 h, the content of As(III) in the soil was reduced to 54.56 %. Compared with the conventional heating treatment, the percentage of stabilized As (residual form) increased by 11.21 %. The localized hot spots formed through the absorption of microwave energy by biochar promote the formation of arsenic-containing mineral crystals (FeAsO4 and Fe3AsO7), thus enhancing the immobilization efficiency. In addition, microwave-induced electron transfer facilitated the oxidation of As(III) to As(V) by surface quinone and carbonyl groups on the Fe-BC. Density functional theory calculation further proved that the surface groups of the Fe-BC had a stronger electron-withdrawing ability under microwave irradiation, thereby promoting the adsorption and immobilization of As(III). This work provided a new perspective on the technology of rapid remediation of heavy metals contaminated soil using biochar.
RESUMO
INTRODUCTION: Depression is a major global health problem, with high prevalence rates of depressive symptoms observed among the elderly population in China, particularly exacerbating in rural areas. Due to a lack of professional mental health training and inadequate psychotherapy capacity within primary medical staff, rural elderly individuals grappling with depressive symptoms often encounter challenges in receiving timely diagnosis and treatment. In this landscape, the modified behavioural activation treatment (MBAT) emerges as a promising approach due to its practicality, ease of therapist training and application, patient acceptability, and broad applicability. However, existing evidence for MBAT mainly hails from developed countries, leaving a gap in its adaptation and implementation within rural China. This study aims to develop an MBAT training programme for primary medical staff to manage depressive symptoms among rural elderly and evaluate its effectiveness. METHODS AND ANALYSIS: A cluster randomised controlled trial will be conducted in 10 randomly selected township hospitals in Lengshuijiang and Lianyuan, Hunan Province. We aim to recruit 150 participants, with 5 township hospitals selected for each group, each consisting of 15 participants. The intervention group will implement the MBAT training programme, while the control group will receive usual care training programme. Depressive symptoms, psychosocial functioning, quality of life and satisfaction will be measured at baseline, immediately post-intervention, and at 3 and 6 months post-intervention. Effectiveness will be assessed using linear or generalised linear mixed models. ETHICS AND DISSEMINATION: This study has obtained approval from the Institutional Review Board of the Third Xiangya Hospital, Centre South University (No.: 2022-S261). Results will be disseminated through publication in international peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300074544.
Assuntos
Depressão , População Rural , Humanos , China , Depressão/terapia , Idoso , Ensaios Clínicos Controlados Aleatórios como Assunto , Feminino , Masculino , Qualidade de Vida , Pessoal de Saúde/educação , Pessoal de Saúde/psicologia , Terapia Comportamental/métodos , Atenção Primária à SaúdeRESUMO
Objectives: Opioid nonadherence represents a significant barrier to cancer pain treatment efficacy. However, there is currently no effective prediction method for opioid adherence in patients with cancer pain. We aimed to develop and validate a machine learning (ML) model and evaluate its feasibility to predict opioid nonadherence in patients with cancer pain. Methods: This was a secondary analysis from a cross-sectional study that included 1195 patients from March 1, 2018, to October 31, 2019. Five ML algorithms, such as logistic regression (LR), random forest, eXtreme Gradient Boosting, multilayer perceptron, and support vector machine, were used to predict opioid nonadherence in patients with cancer pain using 43 demographic and clinical factors as predictors. The predictive effects of the models were compared by the area under the receiver operating characteristic curve (AUC_ROC), accuracy, precision, sensitivity, specificity, and F1 scores. The value of the best model for clinical application was assessed using decision curve analysis (DCA). Results: The best model obtained in this study, the LR model, had an AUC_ROC of 0.82, accuracy of 0.82, and specificity of 0.71. The DCA showed that clinical interventions for patients at high risk of opioid nonadherence based on the LR model can benefit patients. The strongest predictors for adherence were, in order of importance, beliefs about medicines questionnaire (BMQ)-harm, time since the start of opioid, and BMQ-necessity. Discussion. ML algorithms can be used as an effective means of predicting adherence to opioids in patients with cancer pain, which allows for proactive clinical intervention to optimize cancer pain management. This trial is registered with ChiCTR2000033576.