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1.
Acta Pharmacol Sin ; 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38992119

RESUMEN

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

2.
RSC Adv ; 14(32): 22877-22881, 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39035717

RESUMEN

Cellular mechanical force plays a crucial role in numerous biological processes, including wound healing, cell development, and metastasis. To enable imaging of intercellular tension, molecular tension probes were designed, which offer a simple and efficient method for preparing Au-DNA intercellular tension probes with universal applicability. The proposed approach utilizes gold nanoparticles linked to DNA hairpins, enabling sensitive visualization of cellular force in vitro. Specifically, the designed Au-DNA intercellular tension probe includes a molecular spring flanked by a fluorophore-quencher pair, which is anchored between cells. As intercellular forces open the hairpin, the fluorophore is de-quenched, allowing for visualization of cellular force. The effectiveness of this approach was demonstrated by imaging the cellular force in living cells using the designed Au-DNA intercellular tension probe.

3.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(5): 506-511, 2024 May 15.
Artículo en Chino | MEDLINE | ID: mdl-38802912

RESUMEN

OBJECTIVES: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder. METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children's Hospital from January 2018 to August 2023, and a literature review was performed. RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66). CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.


Asunto(s)
Síndrome de Bartter , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Mutación , Humanos , Fibrosis Quística/genética , Fibrosis Quística/complicaciones , Masculino , Femenino , Lactante , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/complicaciones , Preescolar , Niño , Estudios Retrospectivos
4.
Chem Biodivers ; 21(7): e202400980, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38747266

RESUMEN

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.


Asunto(s)
Antineoplásicos Fitogénicos , Ensayos de Selección de Medicamentos Antitumorales , Melanthiaceae , Rizoma , Saponinas , Espirostanos , Humanos , Saponinas/aislamiento & purificación , Saponinas/farmacología , Saponinas/química , Rizoma/química , Melanthiaceae/química , Espirostanos/química , Espirostanos/aislamiento & purificación , Espirostanos/farmacología , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Conformación Molecular , Relación Dosis-Respuesta a Droga
5.
Front Psychiatry ; 15: 1392958, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38751414

RESUMEN

Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

6.
Angew Chem Int Ed Engl ; 63(24): e202400549, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38595043

RESUMEN

The stability of platinum-based alloy catalysts is crucial for the future development of proton exchange membrane fuel cells, considering the potential dissolution of transition metals under complex operating conditions. Here, we report on a Rh-doped Pt3Co alloy that exhibits strong interatomic interactions, thereby enhancing the durability of fuel cells. The Rh-Pt3Co/C catalyst demonstrates exceptional catalytic activity for oxygen reduction reactions (ORR) (1.31 A mgPt -1 at 0.9 V vs. the reversible hydrogen electrode (RHE) and maintaining 92 % of its mass activity after 170,000 potential cycles). Long-term testing has shown direct inhibition of Co dissolution in Rh-Pt3Co/C. Furthermore, tests on proton exchange membrane fuel cells (PEMFC) have shown excellent performance and long-term durability with low Pt loading. After 50,000 cycles, there was no voltage loss at 0.8 A cm-2 for Rh-Pt3Co/C, while Pt3Co/C experienced a loss of 200 mV. Theoretical calculations suggest that introducing transition metal atoms through doping creates a stronger compressive strain, which in turn leads to increased catalytic activity. Additionally, Rh doping increases the energy barrier for Co diffusion in the bulk phase, while also raising the vacancy formation energy of the surface Pt. This ensures the long-term stability of the alloy over the course of the cycle.

7.
Plant Dis ; 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38654537

RESUMEN

Cladosporium spp. are known to be mycoparasites and inhibit phytopathogenic fungi. However, so far, little information is available on the impacts of Cladosporium spp. on powdery mildews. Based on the morphological characteristics and molecular analysis, C. sphaerospermum was identified as a mycoparasite on the wheat powdery mildew fungus (Blumeria graminis f. sp. tritici, Bgt, recently named as B. graminis s. str.). C. sphaerospermum was capable of preventing colony formation and conidial distribution of Bgt. The biomasses of Bgt notably decreased by 1.3, 2.2, 3.6 and 3.8 times at 2 dpi, 4 dpi, 6 dpi and 8 dpi, respectively. In addition, biomasses of C. sphaerospermum at 2 dpi, 4 dpi, 6 dpi and 8 dpi significantly increased to 5.6, 13.9, 18.2 and 67.3 times, respectively. In vitro, C. sphaerospermum exudates significantly impaired appressorial formation of Bgt. Thus, C. sphaerospermum acts as a potential biological control agent by suppressing the formation, distribution and development of Bgt conidia and is a viable alternative for managing the wheat powdery mildew. These results suggest that C. sphaerospermum is an antagonistic parasite of the wheat powdery mildew fungus, and hence, provide new knowledge about the biological control of phytopathogenic fungi.

8.
Sci Prog ; 107(2): 368504241236354, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38614465

RESUMEN

BACKGROUND: Most children with neurocritical illness are at risk of physical, neurocognitive, and psychosocial sequelae and need centralized early rehabilitation care. OBJECTIVE: To identify the effectiveness and safety of centralized early rehabilitation care for children with severe acquired brain injury. METHODS: This is a mixed methods study-an implementation study and single-center retrospective cohort study with historical control. All children with severe acquired brain injury hospitalized in a specialized rehabilitation center in a comprehensive tertiary pediatric hospital between September 2016 and August 2020 were included. Patients treated in the centralized early rehabilitation unit were compared to historical controls dispersed in the normal inpatient rehabilitation ward. The effectiveness outcomes were measured by the Pediatric Cerebral Performance Category (PCPC) scale and the incidence of newly onset comorbidities. The safety outcomes were indicated by the mortality rate and the incidence of unexpected referrals. RESULTS: One hundred seventy-five patients were included. The delta PCPC scores of the first 4 weeks of inpatient rehabilitation in the intervention group were significantly lower than the control group (Z = -2.395, p = 0.017). The PCPC scores at 1 year in the intervention group were significantly reduced as compared to the control group (Z = -3.337, p = 0.001). The incidence of newly onset pneumonia/bronchitis was also decreased in the intervention group (χ2 = 4.517, p = 0.034). No death of patients was recorded, and there was no significant difference in unexpected referral rate between the two groups (χ2 = 0.374, p = 0.541). CONCLUSIONS: The centralized pediatrics early rehabilitation unit is effective and safe for children with severe acquired brain injury. Further multicenter prospective implementation studies on effectiveness, safety, and economic evaluation are needed.


Asunto(s)
Lesiones Encefálicas , Enfermedad Crítica , Humanos , Niño , Estudios Retrospectivos , Estudios Prospectivos , Hospitales , Lesiones Encefálicas/epidemiología
9.
J Orthop Sports Phys Ther ; 54(7): 1-11, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38506711

RESUMEN

OBJECTIVE: To investigate the effectiveness of exercise-based rehabilitation programs compared with nonexercise intervention or no intervention for people with hand osteoarthritis (OA). DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: We searched 5 databases on July 23, 2023. STUDY SELECTION CRITERIA: We included randomized controlled trials that compared the effectiveness of rehabilitation programs that included an exercise component, with nonexercise intervention or no intervention for people with hand OA. DATA SYNTHESIS: Standardized mean differences (SMDs) were pooled using a random-effects model. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. The certainty of the evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: Fourteen trials were included in the meta-analysis (n = 1341 participants). In the immediate term (<24 weeks), there was low-certainty evidence of an effect of exercise-based rehabilitation on improving pain (13 trials; SMD = -0.65; 95% CI: -1.06, -0.25), function (11 trials; SMD = -0.35; 95% CI: -0.54, -0.15), and grip strength (14 trials; SMD = 0.21; 95% CI: 0.03, 0.38). There was moderate-certainty evidence of an effect on reducing stiffness (7 trials; SMD = -0.33; 95% CI: -0.51, -0.16). There was low-certainty evidence of no effect on improving pinch strength and quality of life. For the long term (≥24 weeks), there was low-certainty evidence that exercise-based rehabilitation had no additional effect on improving pain, function, and stiffness. CONCLUSION: Exercise-based rehabilitation improved pain, function, stiffness, and grip strength in people with hand OA in the immediate term; the benefits were not maintained in the long term. J Orthop Sports Phys Ther 2024;54(7):1-11. Epub 20 March 2024. doi:10.2519/jospt.2024.12241.


Asunto(s)
Terapia por Ejercicio , Fuerza de la Mano , Osteoartritis , Humanos , Osteoartritis/rehabilitación , Terapia por Ejercicio/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Articulaciones de la Mano/fisiopatología
11.
Signal Transduct Target Ther ; 9(1): 57, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38438349

RESUMEN

In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.


Asunto(s)
Medicina de Precisión , Humanos , Ensayos Clínicos como Asunto
12.
Chin J Dent Res ; 27(1): 89-99, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38546524

RESUMEN

OBJECTIVE: To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family. METHODS: The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function. RESULTS: The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity. CONCLUSION: A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.


Asunto(s)
Resorción Radicular , Resorción Dentaria , Femenino , Humanos , Proteínas Portadoras , Genes Reguladores , Proteínas de la Membrana , Resorción Radicular/diagnóstico por imagen , Resorción Radicular/genética , Masculino , Pueblos del Este de Asia
13.
FASEB J ; 38(3): e23452, 2024 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-38308640

RESUMEN

Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62-Keap1-Nrf2 pathway affects the development of PAH by mediating autophagy. A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co-IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62-Keap1-Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.


Asunto(s)
Hipertensión Arterial Pulmonar , Animales , Ratas , Autofagia/fisiología , Proliferación Celular , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Monocrotalina , Miocitos del Músculo Liso/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/metabolismo
14.
Artículo en Inglés | MEDLINE | ID: mdl-38357905

RESUMEN

OBJECTIVE: The aim of this study was to construct a multicompartment synchronous rotating bioreactor (MCSRB) for batch-production of homogenized adipose-derived stem cell (ADSC) microspheres and treat neurogenic erectile dysfunction (ED). METHODS: Firstly, an MCSRB was constructed using a centrifugal device and hinged trays. Secondly, influence factors (density, rotational speed) on the formation of ADSC-spheroids were explored. Finally, a neurogenic ED model was established to verify the effectiveness and safety of ADSC-spheroids for ED treatment. RESULTS: An MCSRB promoted ADSCs to gather microspheres, most of which were 90-130 µm in diameter. Supernatant from three-dimensional culture led to a significant increase in cytokine expression in ADSCs and migration rate in human umbilical vein endothelial cells (HUVECs) compared to control groups. The erectile function and pathological changes of the penis were improved in the ADSC-spheroids treatment group compared to the traditional ADSCs treatment group (p < 0.01). CONCLUSION: Efficient, batch, controlled and homogenized production of ADSC stem cell microspheres, and effective improvement of erectile dysfunction in neurogenic rats can be achieved using the MCSRB device.

15.
Carbohydr Polym ; 327: 121705, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38171667

RESUMEN

Utilizing renewable natural resources to construct multifunctional packaging materials is critical to achieving sustainable development in the food packaging industry. In this study, we crafted transparent films with comprehensive UV-shielding and antioxidant properties by blending a multicomponent chitosan complex with polyvinyl alcohol (PVA), subsequently applied to preserve peanut butter. The multicomponent chitosan complex, synthesized from chitosan, ferulic acid (FA), and 5-oxo-3,5-dihydro-2H-thiazolo [3,2-a] pyridine-7-carboxylic acid (TPCA) through direct heating in water, served as the foundation. This chitosan complex was seamlessly blended with PVA, resulting in the creation of a transparent film through the solvent casting method. A meticulous investigation into the chemical structure and physicochemical properties of the blended films was conducted. The FA and TPCA components exhibited robust ultraviolet absorption properties, conferring virtually complete full-band ultraviolet shielding ability to the blend film. Additionally, FA endowed the blended film with significant antioxidant activity. The effectiveness of the chitosan complex/PVA blended film in preserving peanut butter from oxidative spoilage was demonstrated, showcasing its robustness in food preservation. Our research underscores the significance of creating advanced packaging materials from sustainable sources.


Asunto(s)
Antioxidantes , Quitosano , Antioxidantes/química , Alcohol Polivinílico/química , Quitosano/química , Embalaje de Alimentos/métodos , Antibacterianos/química
16.
Eur J Pharmacol ; 965: 176330, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38220139

RESUMEN

Pancreatic cancer (PC) is the most frequently occurring cancer, with few effective treatments and a 5-year survival rate of only about 11%. It is characterized by stiff interstitium and pressure on blood vessels, leading to an increased glycolytic metabolism. PFKFB3 plays an important role in glycolysis, and its products (fructose-2,6-bisphosphate), which are allosteric PFK1 activators, limit the glycolytic rate. In this study, 14 PFKFB3 inhibitors were obtained by virtually screening the FDA-approved compound library. Subsequently, the in-vitro investigations confirmed that Lomitapide and Cabozantinib S-malate exhibit the excellent potential to inhibit PFKFB3. The combined administration of Lomitapide and Gemcitabine at a certain molar ratio indicated an enhanced anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This investigation provides a new treatment strategy for PC therapy.


Asunto(s)
Neoplasias Pancreáticas , Fosfofructoquinasa-2 , Humanos , Fosfofructoquinasa-2/metabolismo , Reposicionamiento de Medicamentos , Detección Precoz del Cáncer , Monoéster Fosfórico Hidrolasas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Glucólisis
17.
J Asian Nat Prod Res ; 26(6): 699-713, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38213072

RESUMEN

Astragaloside IV (AST) has been confirmed to have antiasthmatic effects. However, the underline mechanism is unclear. The study aimed to explore the treatment mechanism of AST based on autophagy of memory T cells. AST treatment significantly decreased the number of T effector cells in asthma mice blood and the nude mice that received AST-treated TCMs had relieved inflammation compared with the untreated group; meanwhile, we found that AST significantly decreased the autophagy level and inhibited OX40/OX40L signal pathway of lymphocytes. The results highlighted that AST regulated autophagy to inhibit differentiation of effector T-cell phenotype.


Asunto(s)
Asma , Autofagia , Inflamación , Saponinas , Linfocitos T , Triterpenos , Animales , Saponinas/farmacología , Asma/tratamiento farmacológico , Triterpenos/farmacología , Triterpenos/química , Ratones , Autofagia/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Inflamación/tratamiento farmacológico , Ratones Desnudos , Estructura Molecular , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos BALB C
18.
J Mol Biol ; 436(2): 168373, 2024 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-37992890

RESUMEN

The G-quadruplex (G4) is a distinct geometric and electrophysical structure compared to classical double-stranded DNA, and its stability can impede essential cellular processes such as replication, transcription, and translation. This study focuses on the BsPif1 helicase, revealing its ability to bind independently to both single-stranded DNA (ssDNA) and G4 structures. The unfolding activity of BsPif1 on G4 relies on the presence of a single tail chain, and the covalent continuity between the single tail chain and the G4's main chain is necessary for efficient G4 unwinding. This suggests that ATP hydrolysis-driven ssDNA translocation exerts a pull force on G4 unwinding. Molecular dynamics simulations identified a specific region within BsPif1 that contains five crucial amino acid sites responsible for G4 binding and unwinding. A "molecular wire stripper" model is proposed to explain BsPif1's mechanism of G4 unwinding. These findings provide a new theoretical foundation for further exploration of the G4 development mechanism in Pif1 family helicases.


Asunto(s)
Adenosina Trifosfato , ADN Helicasas , ADN de Cadena Simple , G-Cuádruplex , Adenosina Trifosfato/química , ADN de Cadena Simple/química , Hidrólisis , Simulación de Dinámica Molecular , ADN Helicasas/química
19.
J Asian Nat Prod Res ; 26(3): 353-371, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37589480

RESUMEN

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.


Asunto(s)
Lesión Renal Aguda , Flavonoides , Transportadores de Anión Orgánico Sodio-Independiente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Transporte Biológico , Flavonoides/farmacología , Flavonoides/química , Transportadores de Anión Orgánico/efectos de los fármacos , Transportadores de Anión Orgánico/metabolismo , Relación Estructura-Actividad , Transportadores de Anión Orgánico Sodio-Independiente/efectos de los fármacos , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 31(6): 1706-1713, 2023 Dec.
Artículo en Chino | MEDLINE | ID: mdl-38071049

RESUMEN

OBJECTIVE: To investigate the effect of Baicalin on the proliferation and pyroptosis of diffuse large B-cell lymphoma cell line DB and its mechanism. METHODS: DB cells were treated with baicalin at different concentrations (0, 5, 10, 20, 40 µmol/L). Cell proliferation was detected by CCK-8 assay and half maximal inhibitory concentration (IC50) was calculated. The morphology of pyroptosis was observed under an inverted microscope, the integrity of the cell membrane was verified by LDH content release assay, and the expressions of pyroptosis-related mRNA and protein (NLRP3, GSDMD, GSDME, N-GSDMD, N-GSDME) were detected by real-time fluorescence quantitative PCR and Western blot. In order to further clarify the relationship between baicalin-induced pyroptosis and ROS production in DB cells, DB cells were divided into control group, baicalin group, NAC group and NAC combined with baicalin group. DB cells in the NAC group were pretreated with ROS inhibitor N-acetylcysteine (NAC) 2 mmol/L for 2 h. Baicalin was added to the combined treatment group after pretreatment, and the content of reactive oxygen species (ROS) in the cells was detected by DCFH-DA method after 48 hours of culture. RESULTS: Baicalin inhibited the proliferation of DB cells in a dose-dependent manner (r=-0.99), and the IC50 was 20.56 µmol/L at 48 h. The morphological changes of pyroptosis in DB cells were observed under inverted microscope. Compared with the control group, the release of LDH in the baicalin group was significantly increased (P<0.01), indicating the loss of cell membrane integrity. Baicalin dose-dependently increased the expression levels of NLRP3, N-GSDMD, and N-GSDME mRNA and protein in the pyroptosis pathway (P<0.05). Compared with the control group, the level of ROS in the baicalin group was significantly increased (P<0.05), and the content of ROS in the NAC group was significantly decreased (P<0.05). Compared with the NAC group, the content of ROS in the NAC + baicalin group was increased. Baicalin significantly attenuated the inhibitory effect of NAC on ROS production (P<0.05). Similarly, Western blot results showed that compared with the control group, the expression levels of pyroptosis-related proteins was increased in the baicalin group (P<0.05). NAC inhibited the expression of NLRP3 and reduced the cleavage of N-GSDMD and N-GSDME (P<0.05). Compared with the NAC group, the NAC + baicalin group had significantly increased expression of pyroptosis-related proteins. These results indicate that baicalin can effectively induce pyroptosis in DB cells and reverse the inhibitory effect of NAC on ROS production. CONCLUSION: Baicalin can inhibit the proliferation of DLBCL cell line DB, and its mechanism may be through regulating ROS production to affect the pyroptosis pathway.


Asunto(s)
Linfoma de Células B Grandes Difuso , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Piroptosis , Línea Celular , ARN Mensajero
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