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1.
Int J Biol Sci ; 20(14): 5531-5547, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39494341

RESUMEN

The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise. Therefore, it has become a major concern health issue worldwide. T2DM leads to various complications, including metabolic-associated fatty liver disease (MAFLD). However, comprehensive studies on MAFLD as a diabetic complication at different stages are still lacking. Using advanced single-cell RNA-seq technology, we explored changes of livers in two T2DM murine models. Our findings revealed that increase activation of hepatic stellate cells (HSCs) exacerbated the development of MAFLD to steatohepatitis by upregulating transforming growth factor ß1 induced transcript 1 (Tgfb1i1). Upregulated thioredoxin-interacting protein (Txnip) contributed to hepatocyte damage by impairing reactive oxygen species clearance. Additionally, the capillarization of liver sinusoidal endothelial cells correlated with Fabp4 overexpression in endothelial cells. A novel subset of Kupffer cells (KCs) that expressed Cd36 exhibited an activated phenotype, potentially participating in inflammation in the liver of diabetic mice. Furthermore, ligand-receptor pair analysis indicated that activated HSCs interacted with hepatocytes or KCs through Thbs2 and Lamb2 in late-stage diseases. The reduction in cell-cell interactions within hepatocytes in diabetic mice, reflects that the mechanisms regulating liver homeostasis is disrupted. This research underscores the importance of dynamics in diabetic MAFLD, and provides new insights for targeted therapies.


Asunto(s)
Diabetes Mellitus Tipo 2 , Células Estrelladas Hepáticas , Hígado , Animales , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Ratones , Hígado/metabolismo , Hígado/patología , Células Estrelladas Hepáticas/metabolismo , Masculino , Hepatocitos/metabolismo , Macrófagos del Hígado/metabolismo , Análisis de Secuencia de ARN , Ratones Endogámicos C57BL , Diabetes Mellitus Experimental/metabolismo , Análisis de la Célula Individual , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Trombospondinas/metabolismo , Trombospondinas/genética
2.
PLoS One ; 19(10): e0311491, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39374217

RESUMEN

BACKGROUND: Reducing exposure to risk factors and screening represent 2 major approaches to gastric cancer (GC) prevention, but public knowledge GC risk factors and screening behaviour remain unknown. We aimed to investigate public awareness of GC risk factors, adherence to screening, and barriers hindering screening practices in China. METHODS: This community-based household survey was conducted within Shijiazhuang, China, and 1490 residents were recruited through a multistage stratified cluster random sampling approach. A self-administered questionnaire was completed which consisted of three sections: demographics, awareness of GC risk factors, and personal screening behaviours. Factors associated with knowledge of risk factors and screening behaviours were evaluated using binary logistic regression analysis. RESULTS: The mean risk factor awareness score of 12 (7, 15) revealed insufficient knowledge in 51.1% of participants. Dietary lifestyle factors were better understood than physical activity and weight-related factors. Marital status (OR 1.967; 95% CI 1.415 to 2.734), higher income (OR 1.197; 95% CI 1.010 to 1.418), and a history of upper gastrointestinal problems (OR 0.048; 95% CI 1.002 to 1.311) were associated with higher awareness. Merely 21.5% underwent GC screening, with higher rates linked to older age (OR 1.642; 95% CI 1.418 to 1.902), higher education (OR 1.398; 95% CI 1.176 to 1.662), a history of upper gastrointestinal problems (OR 3.842; 95% CI 2.833 to 5.209), and moderate (OR 2.077; 95% CI 1.352 to 3.191) and high (OR 2.529; 95% CI 1.311 to 4.878) perceived GC risk. Notably, participants commonly refused gastroscopy due to the absence of symptoms or signs. CONCLUSIONS: In Shijiazhuang, more than half of participants demonstrated inadequate knowledge of GC risk factors, and screening participation rates were remarkably low. This emphasizes the need for targeted interventions to enhance GC awareness and significantly improve screening rates.


Asunto(s)
Detección Precoz del Cáncer , Conocimientos, Actitudes y Práctica en Salud , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/prevención & control , Masculino , China/epidemiología , Femenino , Persona de Mediana Edad , Factores de Riesgo , Adulto , Anciano , Encuestas y Cuestionarios , Detección Precoz del Cáncer/estadística & datos numéricos , Detección Precoz del Cáncer/psicología , Tamizaje Masivo , Adulto Joven
3.
J Int Med Res ; 52(10): 3000605241281425, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39387211

RESUMEN

OBJECTIVE: Multidisciplinary rehabilitation facilitates post-stroke functional recovery, but is associated with resource and accessibility barriers. This study evaluated the combination of a wearable device-assisted system (WEAR) and conventional therapy for post-stroke rehabilitation. METHODS: This randomized, controlled, parallel group, clinical trial was conducted at two rehabilitation centers. A WEAR system was developed featuring sensors and application program-embedded smartphones. Stroke patients within 12 weeks of onset and modified Rankin Scale (mRS) scores of 2 to 4 were randomized into a wearable group (WG, WEAR + conventional rehabilitation) or control group (CG, conventional rehabilitation) for 90 days. The primary outcome was mRS score changes within 90 days. RESULTS: Among 127 stroke patients enrolled (76 men [59.8%]; mean age: 57.5 years), 63 and 64 patients were randomized to WG and CG, respectively. Both groups showed significant improvements in mRS scores. Between-group repeated measures analysis adjusted for sex, age and number of rehabilitation sessions showed greater improvement in mRS scores within 90 days in the WG than in the CG (estimate: 0.73). CONCLUSIONS: This combined WEAR and conventional rehabilitation approach may improve post-stroke functional recovery compared with conventional rehabilitation alone. The WEAR system permits remote monitoring and recording of rehabilitation in various settings.This clinical trial was retrospectively registered at www.clinicaltrials.gov with the Unique Identifier NCT04997408.


Asunto(s)
Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Dispositivos Electrónicos Vestibles , Humanos , Masculino , Femenino , Persona de Mediana Edad , Rehabilitación de Accidente Cerebrovascular/métodos , Rehabilitación de Accidente Cerebrovascular/instrumentación , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/terapia , Anciano , Resultado del Tratamiento , Recuperación de la Función , Adulto , Teléfono Inteligente
4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(5): 1566-1570, 2024 Oct.
Artículo en Chino | MEDLINE | ID: mdl-39479849

RESUMEN

OBJECTIVE: To explore the value of REG3α, sST2 and TNFR1 in peripheral blood for risk stratification and prognostic evaluation of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: From January 2020 to March 2022, 70 children with aGVHD after allo-HSCT in the First Affiliated Hospital of Zhengzhou University were selected as the research objects, of which 50 cases were mild aGVHD (grade I-II) and 20 cases were severe aGVHD (grade III-IV). 30 healthy children who underwent physical examinations in our hospital during the same period were selected as the control group. Luminex platform was used to detect the protein expression levels of REG3α, sST2 and TNFR1 during aGVHD occurrence, and the differences between the three groups were analyzed by one-way ANOVA. According to the outcome of aGVHD treatment within 28 days, the patients were divided into a good prognosis group of 58 cases and a poor prognosis group of 12 cases. The ROC curve was used to analyze the value of REG3α, sST2 and TNFR1 in predicting the prognosis of children with aGVHD. RESULTS: The peripheral blood levels of REG3α, sST2 and TNFR1 in the mild aGVHD and severe aGVHD groups were significantly higher than those in the control group (P <0.05), and those in the severe aGVHD group were significantly higher than those in the mild aGVHD group (P <0.05). Compared with the good prognosis group, the peripheral blood levels of REG3α, sST2 and TNFR1 in the poor prognosis group were significantly higher ( t =9.27,3.33,2.97; P <0.01). ROC curve analysis showed that the area under the curve (AUC), sensitivity and specificity of the combined detection of REG3α, sST2 and TNFR1 in predicting the prognosis of children with aGVHD were higher than those of the above indicators detected alone or in pairs. CONCLUSION: The expression levels of REG3α, sST2 and TNFR1 were related to the severity of aGVHD. The combination of REG3α, sST2 and TNFR1 has a high clinical value in predicting the prognosis of children with aGVHD, which is expected to provide a reliable reference for clinical evaluation of the prognosis of children with aGVHD.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Receptores Tipo I de Factores de Necrosis Tumoral , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Pronóstico , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Niño , Trasplante Homólogo , Proteínas Asociadas a Pancreatitis , Masculino , Femenino , Medición de Riesgo , Adolescente
5.
Physiol Behav ; 288: 114716, 2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39424023

RESUMEN

BACKGROUND: Protein ubiquitination is a common post-translational modification involved in protein degradation and various life processes in cells. NEDL1 is a ubiquitin ligase that is highly expressed primarily in the brain. However, the functions of NEDL1 in social approach/novelty preference, anxiety, learning and memory remain poorly understood. METHODS: Nedl1 knockout mice (Nedl1-/-) and wild-type mice (Nedl1+/+) were tested using three-chamber test, elevated plus maze, and Barnes maze. Then, brain tissue was stained, and blood was collected for metabolic analysis. RESULTS: Compared with Nedl1+/+ mice, Nedl1-/- mice showed no differences in social approach/novelty preference and anxiety behavior. Nedl1-/- mice displayed impaired learning and memory. Nedl1 knockout did not affect the number of neurons and oligodendrocytes in the hippocampus. Astrocytes proliferated in the hippocampus of Nedl1-/- mice. The amino acid metabolism of Nedl1+/+and Nedl1-/- mice is different, especially the increase in proline and tryptophan. CONCLUSION: This study showed that Nedl1 knockout impaired learning and memory, which may be related to astrocyte proliferation and amino acid metabolism change. Nedl1 knockout did not affect social style/novelty preference and anxiety behavior in mice. The preliminary study of NEDL1 in neurobehavioral function could help understand the role of NEDL1 in the nervous system.

6.
Hu Li Za Zhi ; 71(5): 79-88, 2024 Oct.
Artículo en Chino | MEDLINE | ID: mdl-39350712

RESUMEN

BACKGROUND: Concurrent with population ageing, falls have become a significantly more challenging public health issue among older adults. Three years of data collected recently from a nursing home in northern Taiwan reveals an increasing trend in fall density that is primarily associated with aging, physiological decline, chronic diseases, polypharmacy, osteoporosis, and lack of exercise. The percentage of nursing home residents at high risk of falls is currently at 12.6%, and the fall rate has been reported as reaching as high as 30% annually. PURPOSE: A fall prevention program was implemented to reduce the fall incidence rate to 18%, with secondary goals of improving fall prevention awareness, behavior, self-efficacy, lower limb muscle strength, balance, and gait by 10% on average, respectively, between pre-test and post-test. RESOLUTION: From September 30, 2023 to February 29, 2024, a health promotion activity and fall prevention exercise course were implemented using an interdisciplinary team collaboration model over a six-week period, providing individualized exercise for the participants. RESULTS: The study included 20 older adults with an average age of 88 years. Most (90%; n = 18) had chronic diseases, 25% (n = 5) were on more than nine medications, 70% (n = 14) had reduced bone mass, and 40% (n = 8) were at high risk of falls, with a fall incidence rate of 30% during the immediately preceding year. Post-intervention, the fall incidence rate dropped to 5%, fall prevention awareness, behavior, and self-efficacy increased by 18.3%, and lower limb muscle strength, balance, and gait improved by 11.7%. The post-test results in fall prevention awareness, behavioral changes, self-efficacy, and lower limb strength, balance, and gait were all significantly better than pre-test results, with all results achieving statistical significance. CONCLUSIONS: The project results support the positive effects of the developed intervention effectively on elderly physical fitness and fall risk, providing valuable insights for the implementation of fall prevention strategies in nursing homes.


Asunto(s)
Accidentes por Caídas , Cuidados a Largo Plazo , Humanos , Accidentes por Caídas/prevención & control , Anciano , Anciano de 80 o más Años , Femenino , Masculino , Casas de Salud , Grupo de Atención al Paciente
7.
Int J Nanomedicine ; 19: 9035-9053, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39253060

RESUMEN

Background: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism. Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI. Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-ß (TGF-ß) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-ß1in MI rats. Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-ß pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair.


Asunto(s)
Exosomas , MicroARNs , Infarto del Miocardio , Proteína Fosfatasa 2 , Animales , MicroARNs/sangre , MicroARNs/genética , Infarto del Miocardio/sangre , Infarto del Miocardio/terapia , Infarto del Miocardio/genética , Exosomas/metabolismo , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Fibrosis , Daño por Reperfusión Miocárdica/sangre , Daño por Reperfusión Miocárdica/terapia , Miocardio/metabolismo , Precondicionamiento Isquémico/métodos , Precondicionamiento Isquémico Miocárdico/métodos
8.
Inorg Chem ; 63(38): 17367-17371, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39229960

RESUMEN

Recently, chiral organic-inorganic hybrid metal halides have attracted considerable interest as promising multifunctional materials, benefiting from their diverse structures and tunable photophysical properties. Herein, by introducing the chiral ligand methylbenzylamine (R-/S-MBA) and alloying Sn4+ cation, a series of tellurium-based halides R-/S-MBA2SnxTe1-xCl6 (x = 0, 0.125, 0.2, 0.365 and 0.54) with second-harmonic generation (SHG) effect and photoluminescence (PL) properties are successfully synthesized. Their optical bandgaps are determined to be 2.48-2.6 eV. Specifically, the introduction of chiral organic cations could break the structural symmetry and cause the tellurium halide to crystallize in the chiral space group. The incorporation of isovalent Sn4+ into the chiral host tellurium halides results in the increase in octahedral distortion, thereby promoting host intrinsic self-trapped emission that originates from the interconfigurational 3P0,1 → 1S0 transitions of Te4+. Consequently, the as-prepared Sn4+ doped halides, R-/S-MBA2SnxTe1-xCl6 (x = 0.365, 0.54), exhibit not only SHG response but also bright orange fluorescence. This study provides an effective strategy for designing chiral multifunctional materials.

9.
Stat Med ; 43(24): 4684-4701, 2024 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-39189687

RESUMEN

Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD) that causes a significant burden in caregiving and medical costs. Clinically, the diagnosis of MCI is determined by the impairment statuses of five cognitive domains. If one of these cognitive domains is impaired, the patient is diagnosed with MCI, and if two out of the five domains are impaired, the patient is diagnosed with AD. In medical records, most of the time, the diagnosis of MCI/AD is given, but not the statuses of the five domains. We may treat the domain statuses as missing variables. This diagnostic procedure relates MCI/AD status modeling to multiple-instance learning, where each domain resembles an instance. However, traditional multiple-instance learning assumes common predictors among instances, but in our case, each domain is associated with different predictors. In this article, we generalized the multiple-instance logistic regression to accommodate the heterogeneity in predictors among different instances. The proposed model is dubbed heterogeneous-instance logistic regression and is estimated via the expectation-maximization algorithm because of the presence of the missing variables. We also derived two variants of the proposed model for the MCI and AD diagnoses. The proposed model is validated in terms of its estimation accuracy, latent status prediction, and robustness via extensive simulation studies. Finally, we analyzed the National Alzheimer's Coordinating Center-Uniform Data Set using the proposed model and demonstrated its potential.


Asunto(s)
Algoritmos , Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Disfunción Cognitiva/diagnóstico , Enfermedad de Alzheimer/diagnóstico , Modelos Logísticos , Simulación por Computador , Modelos Estadísticos , Anciano
10.
Orphanet J Rare Dis ; 19(1): 299, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39148107

RESUMEN

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.


Asunto(s)
Sirolimus , Humanos , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Niño , Femenino , Adolescente , Preescolar , Adulto , Masculino , Lactante , Adulto Joven , Persona de Mediana Edad , Recién Nacido , Anciano , Esclerosis Tuberosa/tratamiento farmacológico , Linfangioleiomiomatosis/tratamiento farmacológico , Estudios Prospectivos
11.
Bioorg Chem ; 152: 107744, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39213799

RESUMEN

Substrate access tunnel engineering is a useful strategy for enzyme modification. In this study, we improved the catalytic performance of Fe-type Nitrile hydratase (Fe-type NHase) from Pseudomonas fluorescens ZJUT001 (PfNHase) by mutating residue Q86 at the entrance of the substrate access tunnel. The catalytic activity of the mutant PfNHase-αQ86W towards benzonitrile, 2-cyanopyridine, 3-cyanopyridine, and 4-hydroxybenzonitrile was enhanced by 9.35-, 3.30-, 6.55-, and 2.71-fold, respectively, compared to that of the wild-type PfNHase (PfNHase-WT). In addition, the mutant PfNHase-αQ86W showed a catalytic efficiency (kcat/Km) towards benzonitrile 17.32-fold higher than the PfNHase-WT. Interestingly, the substrate preference of PfNHase-αQ86W shifted from aliphatic nitriles to aromatic nitrile substrates. Our analysis delved into the structural changes that led to this altered substrate preference, highlighting an expanded entrance tunnel region, theenlarged substrate-binding pocket, and the increased hydrophobic interactions between the substrate and enzyme. Molecular dynamic simulations and dynamic cross-correlation Matrix (DCCM) further supported these findings, providing a comprehensive explanation for the enhanced catalytic activity towards aromatic nitrile substrates.


Asunto(s)
Hidroliasas , Nitrilos , Pseudomonas fluorescens , Pseudomonas fluorescens/enzimología , Hidroliasas/metabolismo , Hidroliasas/química , Especificidad por Sustrato , Nitrilos/química , Nitrilos/metabolismo , Estructura Molecular , Biocatálisis , Ingeniería de Proteínas
12.
J Org Chem ; 89(17): 12559-12575, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39189641

RESUMEN

The catalytic atroposelective synthesis of N-N axially chiral indolylamides was established via dynamic kinetic resolution, which makes use of chiral Lewis base-catalyzed asymmetric acylation of N-acylaminoindoles as a new type of platform molecule with anhydrides. By this strategy, a series of N-N axially chiral indolylamides were synthesized in overall good yields (up to 98%) with excellent enantioselectivities (up to 99% ee). Moreover, some of these N-N axially chiral indolylamides display some extent of anticancer activity, which demonstrates their potential application in medicinal chemistry. Therefore, this work has not only provided a new strategy for the synthesis of N-N axially chiral monoaryl indoles but also offered a new member of N-N axially chiral monoaryl indoles with configurational stability and promising application, thereby solving the challenges in atroposelective synthesis and application of N-N axially chiral monoaryl indoles.

13.
Appl Environ Microbiol ; 90(9): e0123724, 2024 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-39207158

RESUMEN

Hydroxysteroid dehydrogenases (HSDHs) catalyze the oxidation/reduction of hydroxyl/keto groups of steroids with high regio- or stereoselectivity, playing an essential role in producing optically pure chemicals. In this work, a novel approach was developed to simultaneously improve the stability and activity of 7ß-hydroxysteroid dehydrogenase (7ß-HSDH) by combining B-factor analysis and computer-aided prediction. Several advantageous mutants were identified, and the most promising variant, S51Y/P202Y, exhibited 2.3-fold improvements in catalytic activity, 3.3-fold in half-life at 40°C, and 4.7-fold in catalytic efficiency (kcat/Km), respectively. Structural modeling analysis showed that the shortened reversible oxidation reaction catalytic distance and the strengthened residue interactions compared to the wild type were attributed to the improved stability and activity of the obtained mutants. To synthesize ursodeoxycholic acid cost-effectively by mutant S51Y/P202Y, a NAD-kinase was employed to facilitate the substitution of nicotinamide adenine dinucleotide phosphate (NADP+) with nicotinamide adenine dinucleotide (NAD+) in the whole-cell catalysis system. The substrate 7-ketolithocholic acid (100 mM) was converted completely in 0.5 h, achieving a space-time yield of 1,887.3 g L-1 d-1. This work provided a general target-oriented strategy for obtaining stable and highly active dehydrogenase for efficient biosynthesis. IMPORTANCE: Hydroxysteroid dehydrogenases have emerged as indispensable tools in the synthesis of steroids, bile acids, and other steroid derivatives for the pharmaceutical and chemical industries. In this study, a novel approach was developed to simultaneously improve the stability and activity of a hydroxysteroid dehydrogenase by combining B-factor analysis and computer-aided prediction. This semi-rational method was demonstrated to be highly effective for enzyme engineering. In addition, NAD kinase was introduced to convert NAD+ to NADP+ for effective coenzyme regeneration in the whole-cell multienzyme-catalyzed system. This strategy reduces the significant economic costs associated with externally supplemented cofactors in NADP-dependent biosynthetic pathways.


Asunto(s)
Hidroxiesteroide Deshidrogenasas , Ácido Ursodesoxicólico , Hidroxiesteroide Deshidrogenasas/genética , Hidroxiesteroide Deshidrogenasas/metabolismo , Hidroxiesteroide Deshidrogenasas/química , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/química , Estabilidad de Enzimas , Ingeniería de Proteínas , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , NADP/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Escherichia coli/enzimología , NAD/metabolismo
14.
Front Pharmacol ; 15: 1403943, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39130628

RESUMEN

Background: Alternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder. Methods: To identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets' involvement in islet function. Results: Eight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development. Conclusion: This study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

15.
Front Med (Lausanne) ; 11: 1408342, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39188880

RESUMEN

Background: Surgical patients often experience intraoperative hypothermia or hyperthermia. However, the relationship of intraoperative hypothermia and hyperthermia with postoperative pulmonary infection (PPI) and surgical site infection (SSI) is unclear. Here, we conducted a retrospective cohort study to address these issues. Methods: Adult patients who underwent major non-cardiac surgery under general anesthesia were eligible for the study and were recruited. Three indices of core body temperature under hypothermia (<36°C) and hyperthermia (>37.3°C) were calculated as mentioned in the following: absolute value (0C), duration of exposure (min), and area under the curve (AUC,°C× min). The outcomes were in-hospital PPI and SSI. The risk-adjusted association of intraoperative hypothermia and hyperthermia with PPI and SSI was determined. Results: The absolute value (the nadir value of hypothermia and the peak value of hyperthermia) was not associated with PPI and SSI. PPI was associated with (1) duration: hypothermia >90 min [adjusted odds ratio (aOR): 1.425, 95% confidence interval (CI): 1.131-1.796] and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >3,198 (aOR: 1.390, 95%CI: 1.128-1.731) and hyperthermia >7,945 (aOR: 2.045, 95%CI: 1.138-3.676). SSI was associated with (1) duration: hypothermia > 195 min (aOR: 2.900, 95%CI: 1.703-4.937) and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >6,946 (aOR: 2.665, 95%CI: 1.618-4.390), hyperthermia >7,945 (aOR: 2.619, 95%CI: 1.625-4.220). Interactions were not observed between hyperthermia and hypothermia on the outcomes. Conclusions: It was observed that intraoperative hypothermia and hyperthermia are associated with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

16.
Diagnostics (Basel) ; 14(15)2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39125487

RESUMEN

Timely pathogen identification in bloodstream infections is crucial for patient care. A comparison is made between positive blood culture (BC) pellets from serum separator tubes using a direct identification (DI) method and colonies on agar plates from a short-term incubation (STI) method with a matrix-assisted laser desorption/ionization Biotyper for the evaluation of 354 monomicrobial BCs. Both the DI and STI methods exhibited similar identification rates for different types of bacteria, except for Gram-positive and anaerobic bacteria. The DI method's results aligned closely with the STI method's results for Enterobacterales, glucose-non-fermenting Gram-negative bacilli (GNB), and carbapenem-resistant Enterobacterales. The DI method exhibited high concordance with the conventional method for GNB identification, achieving 88.2 and 87.5% accuracy at the genus and species levels, respectively. Compared with the STI method, the DI method showed a less successful performance for Gram-positive bacterial identification (50.5 vs. 71.3%; p < 0.01). The DI method was useful for anaerobic bacterial identification of slow-growing microorganisms without any need for colony growth, unlike in the STI method (46.7 vs. 13.3%; p = 0.04). However, both methods could not identify yeast in positive BCs. Overall, the DI method provided reliable results for GNB identification, offering many advantages over the STI method by significantly reducing the turnaround time and enabling quicker pathogen identification in positive BCs.

17.
Autoimmun Rev ; 23(6): 103578, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39004157

RESUMEN

Efferocytosis is a crucial process whereby phagocytes engulf and eliminate apoptotic cells (ACs). This intricate process can be categorized into four steps: (1) ACs release "find me" signals to attract phagocytes, (2) phagocytosis is directed by "eat me" signals emitted by ACs, (3) phagocytes engulf and internalize ACs, and (4) degradation of ACs occurs. Maintaining immune homeostasis heavily relies on the efficient clearance of ACs, which eliminates self-antigens and facilitates the generation of anti-inflammatory and immunosuppressive signals that maintain immune tolerance. However, any disruptions occurring at any of the efferocytosis steps during apoptosis can lead to a diminished efficacy in removing apoptotic cells. Factors contributing to this inefficiency encompass dysregulation in the release and recognition of "find me" or "eat me" signals, defects in phagocyte surface receptors, bridging molecules, and other signaling pathways. The inadequate clearance of ACs can result in their rupture and subsequent release of self-antigens, thereby promoting immune responses and precipitating the onset of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. A comprehensive understanding of the efferocytosis process and its implications can provide valuable insights for developing novel therapeutic strategies that target this process to prevent or treat autoimmune diseases.


Asunto(s)
Apoptosis , Enfermedades Autoinmunes , Fagocitos , Fagocitosis , Humanos , Fagocitosis/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Fagocitos/inmunología , Animales , Apoptosis/inmunología , Transducción de Señal/inmunología , Eferocitosis
18.
Stud Health Technol Inform ; 315: 577-578, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39049330

RESUMEN

Taiwan has a well-structured healthcare insurance system that offers accessible medical resources to the public through nominal health insurance fees. Consequently, individuals in need of care willingly pay nominal charges for medical services, including rehabilitation treatment. This study delves into the rehabilitation department of a medical center in southern Taiwan. Despite offering comprehensive traditional rehabilitation services covering neurological, musculoskeletal, pediatric, cardiopulmonary, communication, and swallow disorders, the demand for appointments significantly surpasses the number of available therapists. Therefore, this paper proposes an efficiently method to optimize patient-therapist appointment. With a Complex Conditional Logic that we have designed in this paper, we aim to simplify the scheduling processing for patient seeking appointment either online or via phone calls. More than 50,000 cases have been treated since the system's launch within a year, facilitates hospital resource allocation and enhancing patient medical experiences.


Asunto(s)
Citas y Horarios , Taiwán , Humanos , Eficiencia Organizacional , Centros de Rehabilitación
19.
Stud Health Technol Inform ; 315: 663-664, 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39049371

RESUMEN

In the demanding realm of the Emergency Department, addressing every emergency incident efficiently becomes paramount, with time emerging as a critical factor. This paper is dedicated to investigating innovative approaches aimed at diminishing the preparation time required when a patient arrives at the hospital. Our methodology involves the integration of pre-hospital warning data, a valuable resource provided by the National Science and Technology Center for Disaster Reduction (NCDR), with an advanced flashing light alert system. This integration specifically targets a reduction in preparation time for major traumas, Cerebrovascular Accidents (CVAs), Out-Of-Hospital Cardiac Arrests (OHCAs), and Acute Myocardial Infarctions (AMIs) at the South Medical Center in Taiwan. By streamlining these critical processes, our research endeavors to enhance overall efficiency and responsiveness within emergency medical care, achieving an average preparation time of 6.61 minutes.


Asunto(s)
Servicios Médicos de Urgencia , Taiwán , Humanos , Integración de Sistemas , Sistemas de Comunicación entre Servicios de Urgencia
20.
Artículo en Inglés | MEDLINE | ID: mdl-39083170

RESUMEN

Women who undergo cesarean delivery have reported experiencing mood distress related to the surgery and postoperative pain. Heart rate variability biofeedback (HRVB) training is known to have positive effects on mental health, but its effects on women undergoing cesarean delivery have not yet been determined. This study evaluated the effects of an HRVB training intervention on stress, anxiety, and depression in women undergoing cesarean delivery. We hypothesized that 10 sessions of HRVB training could cumulatively improve emotion regulation in participants. This study was designed as a double-blinded randomized controlled trial involving a total of 86 enrolled women who were then divided into two groups: intervention and control. During their hospitalization, the intervention group underwent HRVB training daily, while both groups received standard perinatal care. Heart rate variability (HRV) was assessed using root mean square of successive differences (RMSSD), standard deviation of normal-to-normal intervals (SDNN), high-frequency power (HF) and low-frequency power (LF). HRV parameters, stress, anxiety, and depression were evaluated at baseline and on the fifth day after childbirth. Intention-to-treat (ITT) analyses examined change over time between groups. Although no significant effects were found for the RMSSD and HF, a significant increase was observed in SDNN (F = 13.43, p = < 0.001, ƞ2 = 0.14), and LF at post-assessment (F = 4.26, p = .04, ƞ2 = 0.05) compared to the control group. Except for the depression variable, stress (F = 6.11, p = .02, ƞ2 = 0.07) and anxiety (F = 8.78, p = .004, ƞ2 = 0.10) significantly decreased compared to the control group on the fifth postpartum day. Furthermore, post-hoc analysis showed that HRVB was more effective in decreasing mild to severe depressive symptoms (F = 7.60, p = .001, ƞ2 = 0.27). The intervention program successfully decreased self-perceived stress and anxiety in the postpartum period and relieved symptoms in more severely depressed participants. Our findings suggest that this program is suitable and beneficial for application in women during the early postpartum period following cesarean delivery.

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